Note: Descriptions are shown in the official language in which they were submitted.
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METHODS AND COMPOUNDS FOR MODULATING
CANNABINOID ACTIVITY
PRIORITY STATEMENT
[0001] This application claims the benefit of U.S. Provisional Appln. No.
60/999,127,
filed October 16, 2007. The entire disclosure of that application is relied on
and incorporated
into this application by reference.
FIELD OF THE INVENTION
[0002] The present disclosure is in the field of medicinal chemistry. More
specifically,
this disclosure relates to the use of certain chemical compounds in methods
for treating pain,
inflammation, neuropathy, neurodegenerative disease, anxiety disorder, motor
function
disorder, fertility disorder, appetite disorder, metabolic disorder, movement
disorder, and
cancer.
BACKGROUND
[0003] Presently, two G;10 protein coupled cannabinoid receptors have been
characterized
in mammals and other organisms: CB 1, a central receptor found in the
mammalian brain and
a number of other sites in peripheral tissues; and CB2, a peripheral receptor
found principally
in cells related to the immune system. Compounds known as cannabinergic
ligands bind to
CB1 and/or CB2 receptors in a subject. In vitro methods for assaying the
ability of a
compound to bind to CB 1 and/or CB2 receptors are known and results from these
assays
correlate with, and predict, the in vivo ability of that compound to bind to,
and thereby
modulate, CB 1 and/or CB2 receptors.
[0004] Despite having a rapid onset of action, the magnitude and duration of
in vivo CB 1
and/or CB2 receptor modulation by cannabinergic ligands are relatively short,
because of a
rapid inactivation process comprising hydrolysis of that cannabinergic ligand.
For example,
anandamide is inactivated by fatty acid amide hydrolase (FAAH)-mediated
hydrolysis.
Although FAAH has also been shown to catalyze hydrolysis of 2-
arachidonoylglycerol in
vitro, a distinct enzyme, mono acylglycerol lipase (also known as MGL, MAG
lipase, or
MAGL) plays the predominant role in catalyzing 2-arachidonoylglycerol
hydrolysis in vivo.
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MGL is a serine hydrolase that converts 2- and 1-monoglycerides to fatty acid
and glycerol
and is a key enzyme responsible for the termination of endocannabinoid
signaling. A need
exists for compounds that inhibit the hydrolytic activity of MGL and FAAH,
thereby
maintaining or increasing the magnitude and duration of cannabinoid receptor
modulation.
SUMMARY OF THE INVENTION
[0005] It has been discovered that certain chemical compounds can inhibit MGL.
This
discovery has been exploited to develop the present application, which
includes novel
compounds and therapeutic compositions for inhibiting MGL, or MGL and FAAH,
methods
for modulating cannabinoid receptors, and methods for treating various
disorders in a subject.
[0006] One aspect of the application is directed to a method of modulating
cannabinoid
receptors in a biological sample. In this method, the level of a cannabinergic
ligand in the
biological sample is measured. Then, the biological sample is contacted with a
compound of
Formula (I), thereby inhibiting an enzyme that hydrolyzes the cannabinergic
ligand. The
level of the cannabinergic ligand in the contacted sample is then measured,
the cannabinoid
receptors being modulated if the level of the cannabinergic ligand in the
contacted sample is
the same or greater than the level of the cannabinergic ligand in the
uncontacted sample.
[0007] In the compound having Formula (I), R-X-Y, Y is selected from the group
consisting of
O
-Sp2Y1 Y2 Y 5
Y3 Y4 Y6 Y7
I! Ili IV
O
W,
i
/Y8 Y9 N \
O QlY13
V VI
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o O 3 4
2 5
N Y13 N Y13
6
Q2 Q2 W 2
and 7
vii VIII
wherein: Y1 is -F, -Cl, -0-alkyl, -0-cycloalkyl, -0-heterocyclic, -0-aryl,
-0-heteroaryl, or -0-adamantyl;
Y2 is -H, -OH, -NH2, -OMe, -OEt, -CF3, -C=CH, -CH2-C=CH, -CH=CH2,
fluoroalkyl, -C1.5-alkyl, -aryl, -alkyl-aryl, -aryl-alkyl, -aryl-alkyl-Y14, -
aryl-heteroaryl,
-aryl-aryl, -heteroaryl, -heteroaryl-alkyl, -heteroaryl-alkyl-Y14i -heteroaryl-
aryl,
-heteroaryl-heteroaryl, -cycloalkyl, -cycloalkyl-alkyl, -cycloalkyl-alkyl-Y14,
-heterocyclic, -heterocyclic-alkyl, -heterocyclic-alkyl-Y14, -adamantyl,
-C1.5-alkyl-Y14, -aryl-Y14, -heteroaryl-Y14, -cycloalkyl-Y14, -heterocyclic-
Y14, or
-adamantyl-Y 14;
Y3 and Y4 are each independently -F, -Cl, or -OH; or Y3 and Y4 taken
together form a ketone;
Y5 is -F, -CONH7, -SO2NH2, -COOH, -COOMe, -COOEt, -CF3, -C=CH,
-CH2-C=CH, -CH=CH2, fluoroalkyl, -C1.5-alkyl, aryl, heteroaryl, cycloalkyl,
heterocyclic, adamantyl, -C1_s-alkyl-Y14, -aryl-Y14, -heteroaryl-Y14, -
cycloalkyl-Y14,
-adamantyl-Y14, or -heterocyclic-Y14;
Y6 and Y7 are each independently -F, -Cl, or -OH;
Y8 is NH, 0, or heterocycle;
Yg is -OY10, -N(Y11)Y12, or heterocycle;
Y10 is alkyl, aryl, benzyl, difluorophenyl, fluorophenyl, heteroaryl,
cycloalkyl,
adamantyl, heterocyclic, -C1.5-alkyl-Y14, -aryl-Y14, -heteroaryl-Y14, -
cycloalkyl-Y14,
-adamantyl-Y14, or -heterocyclic-Y14;
Y11 is -H, -alkyl, -aryl, or -alkyl-aryl;
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Y12 is alkyl, aryl, heteroaryl, cycloalkyl, adamantyl, heterocyclic,
-C1-s-alkyl-Yi4, -C1-5-alkyl-aryl, -C1.5-alkyl-heteroaryl, -aryl-(Y14)1 4,
-heteroaryl-Y14, -cycloalkyl-Y14, -adamantyl-Y14, or -heterocyclic-Y14; or Y11
and Y12
when taken together along with the N to which they are bonded form a 5- or
6-membered saturated heterocylic ring, the ring containing up to one
additional
heteroatom selected from the group consisting of N, 0, and S;
Y13 is -H, -OH, -SH, -NH2, -CN, -N3, -NCS, -NCO, -CONH2, -SO22NH2,
-COOH, -COOMe, -COOEt, -NO2, -CF3, -SO3H, -P(O)(OH)2, -C=CH, -CH2-C=CH,
-CH=CH2, fluoroalkyl, -C1_6-alkyl, aryl, heteroaryl, cycloalkyl, adamantyl,
heterocyclic, -C1_6-alkyl-Y14, -aryl-Y14, -heteroaryl-Y14, -cycloalkyl-Y14,
-adamantyl-Y14, or -heterocyclic-Ylo;
Y14 is -H, -F, -Cl, Br, -I, -OH, -OMe, -OEt, -OPh, -OBn, -SH, -NH2, -CN,
-N3, -NCS, -NCO, -CONH2, -SO2NH2, -COOH, -COOMe, -COOEt, -NO2, -alkyl,
-CF3, -SO3H, -P(O)(OH)7, -C=CH, -CH2-C=CH, -CH=CH2, or -NHCOCH3, or
-CH2OH;
W1 is CH or N if Y13 is not bonded to W1, or W1 is C if Y13 is bonded to W1;
W2 is CH or N if W2 is not bonded to Y13, or W2 is C if W2 is bonded to Y13;
if W2 is N then it can occupy position 4, 5, 6, or 7 in VIII;
QI is -CH2, -0, -S, or -NH if Q1 is not bonded to Y13; Q1 is -CH or -N if Q1
is
bonded to Y13;
Q2 is -SO2, -C(O), or -S(O);
wherein: X is -(CH2)õ-, -(CH2) -A- (CH2)1k-, cycloalkyl, or heterocycle; A is
-CH=CH-, -C=C-, C=O, 0, S, or NH; n is an integer from 0 to 15; j is an
integer from 0 to 10;
and k is an integer from 0 to 10; and wherein R is selected from the group
consisting of
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R5 4
Rl`W~
6~/ / )2
~-
R2 W3 R2 3
1
IX x
R, 5 4 R, 4 3
W4 W3
6~i 5~~
R2 I R2 2
7 ~2 6 Q3
W4 W3 7
8 1
XI XII
4 R1
W
4
R1-.` 5
2 R2 B
6
R2 Q3
1 7
XIII XIV
N -N N N\
!/ ` I N
NN
R, R,
xv xvi 5
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7 g 1 2
R ,W6 W5
R7 R9 R5
9 5 4 5
R6 R4 Rio Alkyl
XVII , and XVIII
wherein: W3 is CH, 0, or N if W3 is not bonded to X or R, or R2; W3 is
C if W3 is bonded to X or R1 or R,; if W3 is N then it can occupy position 1,
2,
3, 4, 5 or 6 in IX, position 2, 3, 4 or 5 in X, position 1, 2, 3 or 4 in XI,
position
2 or 3 in XII, and position 2 or 3 in XIII;
W4 is CH or N if W4 is not bonded to X or RI or R2; W4 is C if W4 is
bonded to X or Ri or R2; if W4 is N then it can occupy position 5, 6, 7 or 8
in
XI, position 4, 5, 6 or 7 in XII and position 4, 5, 6 or 7 in XIII;
W5 is CH or N if W5 is not bonded to X or R4 or R5; W5 is C if W5 is
bonded to X or R4 or R5; if W5 is N then it can occupy position 1, 2, 3, 4 or
5
in XVII;
W6 is CH or N if W6 is not bonded to R6 or R7 or R8 or R9; W6 is C if
W6 is bonded to R6 or R7 or R8 or R9; if W6 is N then it can occupy position
7,
8, 9, 10 or 11 in XVII;
Q3 is CH2, 0, S or NH if Q3 is not bonded to X or R1 or R2; Q3 is CH
or N if Q3 is bonded to X or R1 or R,;
B is adamantyl or heteroadamantyl;
Ri and R2 are each independently -H, -F, -Cl, -Br, -I, -OH, -SH, -NH2,
-CN, -N3, -NCS, -NCO, -CONH2, -SO2NH2, -COOH, -NO2, -CHO, -CF3,
-SO3H, -SO2C1, -SO2F, -O-P(O)(OH)2, -O-P(O)(O-alkyl)2,
-O-P(O)(OH)(O-alkyl), -P(O)(O-alkyl)2, -P(O)(OH)(O-alkyl), -Sn(alkyl)37
-Si(alkyl)3, -C=CH, -CH2-C=CH, -CH=CH2, -alkyl-R3, -cycloalkyl-R3,
-heterocyclic-R3, -aryl-R3, -heteroaryl-R3, -alkyl-cycloalkyl-R3,
-alkyl-heterocyclic-R3, -alkyl-aryl-R3, -alkyl-heteroaryl-R3, -Z-alkyl-R3,
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-Z-cycloalkyl-R3, -Z-heterocyclic-R3, -Z-aryl-R3, -Z-heteroaryl-R3,
-Z-alkyl-cycloalkyl-R3, -Z-alkyl-heterocyclic-R3, -Z-alkyl-aryl-R3,
-Z-alkyl-heteroaryl-R3, -aryl-Z-alkyl-R3, -aryl-Z-cycloalkyl-R3,
-aryl-Z-heterocyclic-R3, -aryl-Z-aryl-R3, -aryl-Z-heteroaryl-R3,
-aryl-Z-alkyl-cycloalkyl-R3, -aryl-Z-alkyl-heterocyclic-R3,
-aryl-Z-alkyl-aryl-R3, -aryl-Z-alkyl-heteroaryl-R3, -CH(alkyl-R3)2,
-C(alkyl-R3)3, -N(alkyl-R3)2, -C(O)N(alkyl-R3)2, -SO2N(alkyl-R3)2, or
adamantyl;
Z is -0, -S, -NH, -C(O), -C(O)O, -OC(O), -C(O)NH, -NHC(O), -SO,
-SO2, -SO2NH, -NHSO2, -SO2O, or -OSO2;
R3 is -H, -F, -Cl, -Br, -I, -Me, -Et, -OH, -OAc, -SH, -NH7, -CN, -N3,
-NCS, -NCO, -CONH2, -SO7NH2, -COON, -NO2, -CHO, -CF3, -SO3H, -SO2F,
-O-P(O)(OH)2, -Sn(alkyl)3, -Si(alkyl)3, -OSi(alkyl)3, -C-CH, -CH2-C-CH, or
-CH=CH2;
R4, R5, R6, R7, R8, and R9 are each independently -H, -F, -Cl, -Br, -I,
-OH, -OMe, -OEt, -OCH2OCH3, -OAc, -SH, -SMe, -SEt, -NH2, -CN, -N3,
-NCS, -NCO, -CONH2, -SO7NH2, -COOH, -NO2, -CHO, -CF3, -SO3H, -SO2F,
-O-P(O)(OH)2, -Sn(alkyl)3, -Si(alkyl)3, -OSi(alkyl)3, -alkyl, or -alkyl-R3;
and
Rio is -H, -F, -Cl, -Br, -I, -OH, -OMe, -OEt, -OAc, -SH, -SMe, -SEt,
-NH2, -CN, -N3, -N-CS' -NCO, -CONH2, -SO2NH2, -COOH, -NO2, -CHO,
-CF3, -SO3H, -SO2F, -O-P(O)(OH)2, -Sn(alkyl)3, -Si(alkyl)3, -OSi(alkyl)3,
-C-CH, -CH2-C=CH, or -CH=CH2; and
wherein: if Y is V, Y8 is 0 or NH, Y9 is OY10 where Y10 is alkyl, cycloalkyl,
heterocyclic, aryl, phenyl, or heteroaryl, and X is -(CH,)n- where n = 0, then
R can not be IX,
X, XI, XII, XIII, or XVIII when one of R1 or R2 is H;
if Y is V, Y5 is 0 or NH, Y9 is OY10 where Y10 is alkyl, cycloalkyl,
heterocyclic, aryl,
phenyl, or heteroaryl, and X is -(CH2)n- where n = 0-3, and R is XVII, then
each of R4, R5,
R6, R7, R8, and Rg can not be H, alkyl, OMe, OEt, F, Cl, Br, I, CN, OH, NO2,
NH2, SH, SMe,
SEt, CONH2, or SO2NH2;
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if Y is V, Y8 is 0 or NH, Y9 is N(Y11)Y12 where Y11 is H and Y12 is alkyl,
cycloalkyl,
heterocyclic, aryl, phenyl, or heteroaryl, or where Y11 and Y12 when taken
together along
with the N to which they are bonded form a 5- or 6-membered saturated
heterocylic ring, X is
-(CH2)n- where n = 0; then R can not be IX, X, XI, XII, XIII, or XVIII when
one of R1 or
R2 is H; and
if Y is V, Y8 is 0 or NH, Y9 is N(Y11)Y12 where Y11 is H and Y12 is alkyl,
cycloalkyl,
heterocyclic, aryl, phenyl, or heteroaryl, or where Y11 and Y12 when taken
together along
with the N to which they are bonded form a 5- or 6-membered saturated
heterocylic ring, X is
-(CH2)n- where n = 0-3, and R is XVII; then each of R4, R5 R6, R7, R8, and R9
can not be H.
alkyl, OMe, OEt, F, Cl, Br, 1, CN, OH, NO2, NH2, SH, SMe, SEt, CONH2, or
SO7NH2.
[0008] In some embodiments, the enzyme inhibited by the compound of Formula
(I) is
MGL and/or FAAH.
[0009] In certain embodiments, the cannabinergic ligand is 2-
arachidonoylglycerol or
anandamide.
[0010] In some embodiments, the CB1 receptor or the CB2 receptor is modulated.
[0011] In still further embodiments, the compound having formula R-X-Y in the
method
of modulation is a compound listed in Tables 1 and 2 in the below Examples.
[0012] A further aspect of the disclosure is directed to a method of treating
a neuropathy
in a subject. In this method, a therapeutically effective amount of a compound
of Formula (I)
is administered to the subject. The administration of the compound treats the
neuropathy of
the subject. In some embodiments, the neuropathy is inflammation, pain,
neuropathic pain,
neuropathic low back pain, complex regional pain syndrome, post trigeminal
neuralgia,
eauralgia, toxic neuropathy, reflex sympathetic dystrophy, diabetic
neuropathy, chronic
neuropathy caused by chemotherapeutic agents, central pain, peripheral pain,
pellagric
neuropathy, alcoholic neuropathy, Beriberi neuropathy, or burning feet
syndrome. In
particular embodiments, the compound of Formula (I) is a compound listed in
Tables 1 and 2,
below.
[0013] In yet other embodiments, the neuropathy is a neurodegenerative
disease. In
particular embodiments, the neurodegenerative disease is multiple sclerosis,
Parkinson's
disease, Huntington's chorea, Alzheimer's disease, amyotrophic lateral
sclerosis, memory
disorder, mood disorder, sleep disorder, gastrointestinal motility disorder,
irritable bowel
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syndrome, diarrhea, cardiovascular disease, hypertension, osteoporosis,
osteoarthritis, emesis,
epilepsy, a mental disorder, schizophrenia, depression, glaucoma, cachexia,
insomnia,
traumatic brain injury, spinal cord injury, seizures, excitotoxin exposure,
ischemia, or AIDS
wasting syndrome.
[0014] An additional aspect of the application is directed to a method of
treating a motor
function disorder in a subject. The method comprises administering to the
subject a
therapeutically effective amount of a compound of Formula (I). The
administration of the
compound treats the motor function disorder of the subject. In one embodiment,
the motor
function disorder is Tourette's syndrome. In particular embodiments, the
compound of
Formula (1) is a compound listed in Tables I and 2, below.
[0015] Another aspect of the application is directed to a method of treating
an anxiety
disorder in a subject. The method comprises administering to the subject a
therapeutically
effective amount of a compound of Formula (I). The administration of the
compound treats
the anxiety disorder of the subject. In certain embodiments, the anxiety
disorder is panic
disorder, acute stress disorder, post-traumatic stress disorder, substance-
induced anxiety
disorder, obsessive compulsive disorder, agoraphobia, specific phobia, or
social phobia. In
particular embodiments, the compound of Formula (I) is a compound listed in
Tables 1 and 2,
below.
[0016] An additional aspect of the disclosure is directed to a method of
treating a fertility
disorder in a subject. The method comprises administering to the subject a
therapeutically
effective amount of a compound of Formula (I). The administration of the
compound treats
the fertility disorder of the subject. In particular embodiments, the compound
of Formula (I)
is a compound listed in Tables 1 and 2, below.
[0017] In yet another aspect, the disclosure is directed to a method of
treating an appetite
disorder in a subject. The method comprises administering to the subject a
therapeutically
effective amount of a compound of Formula (I). The administration of the
compound treats
the appetite disorder, the metabolic disorder, or the movement disorder of the
subject. In
particular embodiments, the compound of Formula (I) is a compound listed in
Tables 1 and 2,
below.
[0018] In another aspect, the disclosure is directed to a method of treating a
metabolic
disorder in a subject. The method comprises administering to the subject a
therapeutically
effective amount of a compound of Formula (I). The administration of the
compound treats
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the metabolic disorder of the subject. In particular embodiments, the compound
of Formula
(I) is a compound listed in Tables 1 and 2, below.
[0019] In still another aspect, the disclosure is directed to a method of
treating a
movement disorder in a subject. The method comprises administering to the
subject a
therapeutically effective amount of a compound of Formula (I). The
administration of the
compound treats the movement disorder of the subject. In particular
embodiments, the
compound of Formula (I) is a compound listed in Tables 1 and 2, below.
[0020] Another aspect of the disclosure is directed to a method of treating
cancer in a
subject. The method comprising administering to the subject a therapeutically
effective
amount of a compound of Formula (I). The administration of the compound treats
the cancer
of the subject. In particular embodiments, the compound of Formula (1) is a
compound listed
in Tables 1 and 2, below.
[0021] Another aspect of the disclosure is directed to sulfonyl chlorides. In
certain
embodiments, the sulfonyl chloride is selected from the group consisting of
/ \ (CH2)7-SO2CI
Bn0 \ (CH2)7-SO2Ci
BnO
(CH2)7-SO2CI -
OBn 0 (CH2)4 SO2C) and BnO \ (CH2)5-SO2CI
[0022] Still another aspect of the disclosure is directed to sulfonyl
fluorides. In some
embodiments, the sulfonyl fluoride is selected from the group consisting of
(CH2)7-SO2F (CH2)7-SO2F
BnO \ (CH2)7-SO2F
BnO , OBn
r\ (CH2)7-SOzF
BnO (CH2)5-SO2F HO (CH2)7-SO2F
HO
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Q(CH2)7-SO2F
OH HO \ (CH2)5-SO2F r O-(CH2)4 SO2F
and
[0023] Yet another aspect of the disclosure is directed to trifluoromethyl
ketones. In
particular embodiments, the trifluoromethyl ketone is selected from the group
consisting of
BnO \ O-(CH2)3-000F3 BnO O-(CH2)4-000F3 BnO r\ O-(CH2)5-000F3
r_\ o-(CH2)3-cocF3 r \ O-(CH2)q COCF3
Bn0 /\ O-(CH2)6-000F3
BnO BnO
Q_O_(CH2)5COCF3 J_O-(CH2)3-COCF3 Q_O_(CH2)4-COCF3
BnO OBn OBn
Qo_(cH2)5cocF3
&0(0H2)3C0CF3 F \ O-(CH2)4-000F3
OBn
HO 1\ O-(CH2)3-000F3 HO O-(CH2)4000F3 HO O-(CH2)5 COCF3
O-(CH2)3-C-CF3 r\0-(CH2)4-000F3
HO O-(CH2)6-000F3 HO OH
HO HO ,
QO_(CH2)3COCF3 QO_(CH2)5cOCF3
r \ (CH2)3-000F3
OH OH
(CH2)4-COCF3 (CH2)5-000F3 MeO (CH2)4-COCF3
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i o
BnO / CF3 Bn0 CF3
O
O 0
F3C OH F3C OMe
\ \ \ \ C6H,3
HO DMH and HO
[0024] A further aspect of the disclosure is directed to carbamates. In some
embodiments, the carbamate is selected from the group consisting of
\ Ny N Br Nu0 \ ( o
I I
Br 'a O Br l i 0
O
bLoNH
H
O, f N' OCH2OCH3 \
CH3OCH2O~v~DMH H3C CH CH 3
3
O 0
O'J~ NH b~oNH
xCI
CF3 CI
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Br
O 0
ONH 0ANH CHs
H3C NH
\ Br O
O
O NH
bLoH~i q "~
of
O O O
0ANH ONH ONH
cl
CI \ CI CI F F
O O
O NH ONH O
OANH
\ \ I / I
~I
MeO \ OMe
O OMe
O 0
I
bL 1, 0 NH O NH
SCH3 CI
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O 0
bLo bLo N------`
O
AN0_0
and
[0025] In another aspect, the disclosure is directed to ureas. In certain
embodiments, the
urea is selected from the group consisting of
N- N-
(CH2)3-NH-C-NH-CH2 (CH2)3-NH-C-NH
o and o
[0026] In a further aspect, the disclosure is directed to a-Keto-oxadiazoles.
In certain
embodiments, the a-Keto-oxadiazole is selected from the group consisting of
0
N O
6 HO -\\ O J~ %N
and oOBn
[0027] In another aspect, the disclosure is directed to saccharin analogs. In
some
embodiments, the saccharin analog is selected from the group consisting of
01 0
0~4N
I \ 0 N\5~~0 ( \ O
0 and BnO
DETAILED DESCRIPTION
[0028] This application relates to compounds, and enantiomers, diastereomers,
tautomers,
pharmaceutically-acceptable salts, and solvates of those compounds, that
inhibit MGL or
MGL and FAAH, to methods for modulating cannabinoid receptors, to methods for
inhibiting
MGL and FAAH, to processes for the preparation of these compounds and their
enantiomers,
diastereomers, tautomers or pharmaceutically-acceptable salts or solvates, to
pharmaceutical
compositions comprising these compounds and their enantiomers, diastereomers,
tautomers,
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and pharmaceutically-acceptable salts or solvates, and to methods for treating
inflammation,
pain, neuropathy, central nervous system disorders, and neurodegenerative
disorders.
[00291 Throughout this application, various patents, patent applications and
publications
are referenced. The disclosures of these patents, patent applications and
publications in their
entireties are incorporated into this application by reference in order to
more fully describe
the state of the art as known to those skilled therein as of the date of this
application. This
disclosure will govern in the instance that there is any inconsistency between
the patents,
patent applications and publications and this disclosure.
1. Definitions
[00301 The compounds of this disclosure include any and all possible isomers,
stereoisomers, enantiomers, diastereomers, tautomers, pharmaceutically-
acceptable salts, and
solvates thereof. Thus, the terms "compound" and "compounds" as used in this
disclosure
refer to the compounds of this disclosure and any and all possible isomers,
stereoisomers,
enantiomers, diastereomers, tautomers, pharmaceuticall y-acceptable salts, and
solvates
thereof.
[00311 In general, the compositions of the disclosure can be alternately
formulated to
comprise, consist of, or consist essentially of, any appropriate components
disclosed in this
application. The compositions of the disclosure can additionally, or
alternatively, be
formulated so as to be devoid, or substantially free, of any components,
materials,
ingredients, adjuvants or species used in the prior art compositions or that
are otherwise not
necessary to the achievement of the function and/or objectives of the present
disclosure.
[0032] For convenience, certain terms employed in the specification, examples
and
claims are collected here. Unless defined otherwise, all technical and
scientific terms used in
this disclosure have the same meanings as commonly understood by one of
ordinary skill in
the art to which this disclosure belongs. The initial definition provided for
a group or term
provided in this disclosure applies to that group or tern throughout the
present disclosure
individually or as part of another group, unless otherwise indicated.
[0033] The articles "a" and "an" are used in this disclosure to refer to one
or more than
one (i.e., to at least one) of the grammatical object of the article. By way
of example, "an
element" means one element or more than one element.
[00341 The tern "or" is used in this disclosure to mean, and is used
interchangeably with,
the term "and/or," unless indicated otherwise.
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[0035] The term "about" is used in this disclosure to mean a value - or + 20%
of a given
numerical value. Thus, "about 60%" means a value between 60-20% of 60 and
60+20% of
60 (i.e., between 48% and 72%).
[0036] Unless otherwise specifically defined, "alcohol" refers to the general
formula
alkyl-OH and includes primary, secondary and tertiary variations.
[0037) Unless otherwise specifically defined, the terms "alkyl" and "alk"
refer to a
straight or branched chain alkane (hydrocarbon) radical containing from 1 to
15 carbon
atoms. Exemplary "alkyl" groups include, but are not limited to, methyl
("Me"), ethyl ("Et"),
propyl, isopropyl, n-butyl, t-butyl, sec-butyl, isobutyl, pentyl, hexyl,
isohexyl, heptyl, 4,4-
dimethylpentyl, 1,1-dimethylpentyl, 1,2-dimethylpeptyl, octyl, 2,2,4-
trimethylpentyl, nonyl,
decyl, undecyl, dodecyl, and the like. The alkyl group may be optionally
substituted with one
or more substituents, e.g., 1 to 5 substituents, at any available point of
attachment.
Exemplary substituents include, but are not limited to, one or more of the
following groups:
hydrogen, halogen (e.g., a single halogen substituent or multiple halo
substituents forming, in
the latter case, groups such as CF3)1 cyano, nitro, CF3, OCF3, cycloalkyl,
alkenyl,
cycloalkenyl, alkynyl, heterocycle, aryl, ORa, SRa, S(=O)Rej S(=0)2Re,
P(=O)2Re,
S(=O)2ORe, P(=O)2ORe, NRbR, NRbS(=O)2Re, NRbP(=O)2Re, S(=O)2NRbRe,
P(=O)2NRbRe,
C(=O)ORd, C(=O)Ra, C(=O)NRbRC, OC(=O)Ra, OC(=O)NRbRcj NRbC(=O)ORe,
NRdC(=O)NRbRcj NRdS(=O)2NRbRe, NRdP(=O)2NRbRe, NRbC(=O)Ra, or NRbP(=O)2Re,
wherein each Ra is hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl,
alkynyl, heterocycle, or
aryl; Rb, Re and Rd are each independently hydrogen, alkyl, cycloalkyl,
heterocycle, aryl, or
said Rb and R, together with the N to which they are bonded optionally form a
heterocycle or
substituted heterocycle; and each Re is alkyl, cycloalkyl, alkenyl,
cycloalkenyl, alkynyl,
heterocycle, or aryl. In the aforementioned exemplary substituents, groups
such as alkyl,
cycloalkyl, alkenyl, alkynyl, cycloalkenyl, heterocycle and aryl can
themselves be optionally
substituted. The term "Ci-C,,-alkyl" refers to a straight or branched chain
alkane
(hydrocarbon) radical containing from 1 to n carbon atoms. For example, the
term
"CI-C5-alkyl" refers to a straight or branched chain alkane (hydrocarbon)
radical containing
from 1 to 5 carbon atoms, such as methyl, ethyl, propyl, isopropyl, n-butyl, t-
butyl, isobutyl,
etc.
[0038] Unless otherwise specifically defined, the term "alkenyl" refers to a
straight or
branched chain hydrocarbon radical containing from 2 to 15 carbon atoms and at
least one
16
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carbon-carbon double bond. Exemplary such groups include, but are not limited
to, ethenyl
(also called "vinyl"), alkyl, propenyl, crotyl, 2-isopentenyl, allenyl,
butenyl, butadienyl,
pentenyl, pentadienyl, 3(1,4-pentadienyl), hexenyl and hexadienyl. The alkenyl
group may
be optionally substituted with one or more substituents, e.g., I to 5
substituents, at any
available point of attachment. Exemplary substituents include, but are not
limited to, alkyl or
substituted alkyl, as well as those groups recited above as exemplary alkyl
substituents. The
exemplary substituents can themselves be optionally substituted.
[0039] Unless otherwise specifically defined, the term "alkynyl" refers to a
straight or
branched chain hydrocarbon radical containing from 2 to 15 carbon atoms and at
least one
carbon-carbon triple bond. Exemplary such groups include, but are not limited
to, ethynyl,
propynyl and butynyl. The alkynyl group may be optionally substituted with one
or more
substituents, e.g., 1 to 5 substituents, at any available point of attachment.
Exemplary
substituents include, but are not limited to, alkyl or substituted alkyl, as
well as those groups
recited above as exemplary alkyl substituents. The exemplary substituents can
themselves be
optionally substituted.
[0040] Unless otherwise specifically defined, the term "aryl" refers to
cyclic, aromatic
hydrocarbon groups that have I to 5 aromatic rings, including monocyclic or
bicyclic groups
such as phenyl, biphenyl or naphthyl. Where containing two or more aromatic
rings
(bicyclic, etc.), the aromatic rings of the aryl group may be joined at a
single point (e.g.,
biphenyl), or fused (e.g., naphthyl, phenanthrenyl and the like). The aryl
group may be
optionally substituted by one or more substituents, e.g., 1 to 5 substituents,
at any point of
attachment. Exemplary substituents include, but are not limited to, nitro,
cycloalkyl or
substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, cyano,
alkyl, fused cyclic
groups, fused cycloalkyl, fused cycloalkenyl, fused heterocycle, and fused
aryl, and those
groups recited above as exemplary alkyl substituents. The substituents can
themselves be
optionally substituted.
[0041] Unless otherwise specifically defined, the term "cycloalkyl" refers to
a fully
saturated cyclic hydrocarbon group containing from 1 to 4 rings and 3 to 8
carbons per ring.
Exemplary such groups include, but are not limited to, cyclopropyl,
cyclobutyl, cyclopentyl,
cyclohexyl, cycloheptyl, adamantyl, etc. The cycloalkyl group may be
optionally substituted
with one or more substituents, e.g., 1 to 5 substituents, at any available
point of attachment.
Exemplary substituents include, but are not limited to, nitro, cyano, alkyl,
spiro-attached or
fused cyclic substituents, spiro-attached cycloalkyl, spiro-attached
cycloalkenyl, spiro-
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attached heterocycle, fused cycloalkyl, fused cycloalkenyl, fused heterocycle,
fused aryl, and
those groups recited above as exemplary alkyl substituents. The substituents
can themselves
be optionally substituted.
[0042] Unless otherwise specifically defined, the term "adarnantyl" includes,
but is not
limited to, 1-adamantyl, 2-adamantyl, and 3-adamantyl. The adamantyl group may
be
optionally substituted with the groups recited as exemplary cycloalkyl
substituents.
[0043) Unless otherwise specifically defined, the tenn "cycloalkenyl" refers
to a partially
unsaturated cyclic hydrocarbon group containing 1 to 4 rings and 3 to 8
carbons per ring.
Exemplary such groups include, but are not limited to, cyclobutenyl,
cyclopentenyl,
cyclohexenyl, etc. The cycloalkenyl group may be optionally substituted with
one more
substituents, e.g., 1 to 5 substituents, at any available point of attachment.
Exemplary
substituents include, but are not limited to, nitro, cyano, alkyl or
substituted alkyl, spiro-
attached or fused cyclic substituents, spiro-attached cycloalkyl, spiro-
attached cycloalkenyl,
spiro-attached heterocycle (excluding heteroaryl), fused cycloalkyl, fused
cycloalkenyl, fused
heterocycle, fused aryl, and those groups recited above as exemplary alkyl
substituents. The
substituents can themselves be optionally substituted.
[0044] Unless otherwise specifically defined, the terms "heterocycle" and
"heterocyclic"
refer to fully saturated, or partially or fully unsaturated, including
aromatic (i.e., "heteroaryl")
cyclic groups (for example, 4 to 7 membered monocyclic, 7 to 11 membered
bicyclic, or 8 to
16 membered tricyclic ring systems) which have at least one heteroatom in at
least one
carbon atom-containing ring. Each ring of the heterocyclic group containing a
heteroatom
may have 1, 2, 3, or 4 heteroatoms selected from nitrogen atoms, oxygen atoms
and/or sulfur
atoms, where the nitrogen and sulfur heteroatoms may optionally be oxidized
and the
nitrogen heteroatoms may optionally be quaternized. The heterocyclic group may
be
attached to the remainder of the molecule at any heteroatom or carbon atom of
the ring or
ring system. Exemplary monocyclic heterocyclic groups include, but are not
limited to,
azetidinyl, pyrrolidinyl, pyrrolyl, pyrazolyl, oxetanyl, dioxanyl, dioxolanyl,
oxathiolanyl,
pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl,
isoxazolinyl,
isoxazolyl, thietanyl, azetidine, diazetidine, thiolanyl, thiazolyl,
thiadiazolyl, thiazolidinyl,
isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuryl, thienyl, oxadiazolyl,
piperidinyl,
piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-
oxoazepinyl, azepinyl,
hexahydrodiazepinyl, 4-piperidonyl, pyridyl, purinyl, pyrazinyl, pyrimidinyl,
pyridazinyl,
triazinyl, triazolyl, tetrazolyl, tetrahydropyranyl, mozpholinyl,
thiamorpholinyl,
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thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, 1,3-dioxolane and
tetrahydro-1,1-
dioxothienyl, and the like. Exemplary bicyclic heterocyclic groups include,
but are not
limited to, indolyl, isoindolyl, benzothiazolyl, benzoxazolyl,
benzoxadiazolyl, benzothienyl,
benzo[d][1,3]dioxolyl, 2,3-dihydrobenzo[b][1,4]dioxinyl, quinuclidinyl,
quinolinyl,
tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl,
indolizinyl,
benzofuryl, benzofurazanyl, chromonyl, coumarinyl, benzopyranyl, cinnolinyl,
quinoxalinyl,
indazolyl, pyrrolopyridyl, furopyridinyl (such as furo[2,3-c]pyridinyl,
furo[3,2-b]pyridinyl]
or furo[2,3-b]pyridinyl), dihydroisoindolyl, dihydroquinazolinyl (such as 3,4-
dihydro-4-oxo-
quinazolinyl), triazinylazepinyl, tetrahydroquinolinyl and the like. Exemplary
tricyclic
heterocyclic groups include, but are not limited to, carbazolyl, benzidolyl,
phenanthrolinyl,
acridinyl, phenanthridinyl, xanthenyl and the like.
[0045] A heterocyclic group may be optionally substituted with one or more
substituents,
e.g., 1 to 5 substituents, at any available point of attachment. Exemplary
substituents include,
but are not limited to, cycloalkyl or substituted cycloalkyl, cycloalkenyl or
substituted
cycloalkenyl, nitro, oxo (i.e., =0), cyano, alkyl or substituted alkyl, spiro-
attached or fused
cyclic substituents at any available point or points of attachment, spiro-
attached cycloalkyl,
spiro-attached cycloalkenyl, spiro-attached heterocycle (excluding
heteroaryl), fused
cycloalkyl, fused cycloalkenyl, fused heterocycle, fused aryl, and those
groups recited above
as exemplary alkyl substituents. The substituents can themselves be optionally
substituted.
[0046] Unless otherwise indicated, any heteroatom with unsatisfied valences is
assumed
to have hydrogen atoms sufficient to satisfy the valences.
[0047] The term "heating" includes, but is not limited to, warming by
conventional
heating (e.g., electric heating, steam heating, gas heating, etc.) as well as
microwave heating.
[0048] The term '`carrier", as used in this disclosure, encompasses carriers,
excipients,
and diluents and means a material, composition or vehicle, such as a liquid or
solid filler,
diluent, excipient, solvent or encapsulating material, involved in carrying or
transporting a
pharmaceutical agent from one organ, or portion of the body, to another organ,
or portion of
the body.
[0049] The phrase "pharmaceutically acceptable" is employed in this disclosure
to refer
to those compounds, materials, compositions, and/or dosage forms which are,
within the
scope of sound medical judgment, suitable for use in contact with the tissues
of human beings
and animals without excessive toxicity, irritation, allergic response, or
other problem or
19
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WO 2009/052320 PCT/US2008/080215
complication, commensurate with a reasonable benefit/risk ratio.
[0050] The term "salt(s)", as employed in this disclosure, denotes acidic
and/or basic salts
fonned with inorganic and/or organic acids and bases.
[0051] The term "treating" with regard to a subject, refers to improving at
least one
symptom of the subject's disorder. Treating can be curing, improving, or at
least partially
ameliorating the disorder.
[0052] The tern "disorder" is used in this disclosure to mean, and is used
interchangeably
with, the terns disease, condition, or illness, unless otherwised indicated.
[0053] The terms "effective amount" and "therapeutically effective amount" as
used in
this disclosure refer to an amount of a compound that, when administered to a
subject, is
capable of reducing a symptom of a disorder in a subject. The actual amount
which
comprises the "effective amount" or "therapeutically effective amount" will
vary depending
on a number of conditions including, but not limited to, the particular
disorder being treated,
the severity of the disorder, the size and health of the patient, and the
route of administration.
A skilled medical practitioner can readily determine the appropriate amount
using methods
known in the medical arts.
[0054] As used in this disclosure, the tern "subject" includes, without
limitation, a
human or an animal. Exemplary animals include, but are not limited to, mammals
such as
mouse, rat, guinea pig, dog, cat, horse, cow, pig, monkey, chimpanzee, baboon,
or rhesus
monkey.
[0055] The tern "administer", "administering", or "administration" as used in
this
disclosure refers to either directly administering a compound or
pharmaceutically acceptable
salt of the compound or a composition to a subject, or administering a prodrug
derivative or
analog of the compound or pharmaceutically acceptable salt of the compound or
composition
to the subject, which can form an equivalent amount of active compound within
the subject's
body.
[0056] The term "prodrug," as used in this disclosure, means a compound which
is
convertible in vivo by metabolic means (e.g., by hydrolysis) to a compound of
Formula (I).
[0057] The term "halogen" as used in this disclosure refers to fluorine,
chlorine, bromine,
and iodine.
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[0058] The terms isolated" and "purified" as used in this disclosure refer to
a component
separated from other components of a reaction mixture or a natural source. In
certain
embodiments, the isolate contains at least about 50%, at least about 55%, at
least about 60%,
at least about 65%, at least about 70%, at least about 75%, at least about
80%, at least about
85%, at least about 90%, at least about 95%, or at least about 98% of the
compound or
pharmaceutically acceptable salt of the compound by weight of the isolate.
[0059] The terra "tautomer" as used in this disclosure refers to compounds
produced by
the phenomenon wherein a proton of one atom of a molecule shifts to another
atom. (March,
Advanced Organic Chemistry: Reactions, Mechanisms and Structures, 4th Ed.,
John Wiley &
Sons, pages 69-74 (1992)).
[0060] The following abbreviations are used in this disclosure and have the
following
definitions: MeCN is acetonitrile; DMF is dim ethylformamide; DMSO is
dimethylsulfoxide;
HPLC is high-performance liquid chromatograpy; THE is tetrahydroftiran; EDTA;
Tris is
tris(hydroxymethyl)aminomethane; TBSCI is t-butyldimethylsilyl Chloride; TBAF
is tetra-n-
butylammonium fluoride; "h" is hour or hours; and "RT" is RT.
2. MGL Inhibitory Compounds
[00611 Certain chemical compounds have been found to inhibit the inactivation
of
cannabinergic ligands by MGL. These compounds may not bind to, or may have
lesser
affinity for, the CB 1 And/or CB2 cannabinoid receptors. Thus, the
physiological action for
such compounds and may not be the direct modulation of the CB 1 and/or CB2
receptors.
[0062] Inhibition of MGL in a subject slows the normal degradation and
inactivation of
endogenous cannabinoid ligands by MGL hydrolysis. This inhibition allows
maintained or
higher levels of those endogenous cannabinergic ligands to remain present in
the subject.
The maintained or higher levels of endocannabinoid ligands provide increased
stimulation of
the cannabinoid CB I and CB2 receptors. The increased stimulation of the
cannabinoid
receptors allows the receptors to produce physiological effects at a
maintained or increased
level. Thus, a compound that inhibits the inactivation of endogenous
cannabinoid ligands by
MGL increases the levels of endocannabinoids, thereby enhancing the activation
of
cannabinoid receptors. The compound does not directly modulate the cannabinoid
receptors
but instead indirectly stimulates the cannabinoid receptors by increasing the
in vivo levels of
endocannabinoid ligands.
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[00631 The inhibition of MGL also enhances the effects of exogenous
cannabinergic
ligands and allows them to stimulate cannabinoid receptors at lower
concentrations as
compared to systems in which MGL action is not inhibited. Thus, inhibition of
MGL also
enhances the effects and duration of action of exogenous cannabinergic
ligands.
[0064] Examples of cannabinergic ligands that bind to CB 1 and/or CB2 include,
but are
not limited to, N-arachidonoyl ethanolamine (also known as anandamide or AEA)
and 2-
arachidonoylglycerol (2-AG) (both endogenous ligands for the cannabinoid CB1
and CB2
receptors), (-)-09-tetrahydrocannabinol (the principal bioactive constituent
of cannabis and
exogenous ligand for the cannabinoid CB 1 and CB2 receptors) and other
synthetic
cannabinergic analogs.
[00651 Marijuana-like cannabinoids, in addition to acting at cannabinoid
receptors, also
affect cellular membranes, and are known to cause undesirable side effects
such as
drowsiness, impairment of monoamide oxidase function, and impairment of non-
receptor
mediated brain function. Thus, the addictive and psychotropic properties of
some
cannabinoids limit their therapeutic value. Compounds that inhibit MGL
activity provide an
alternative mechanism for stimulating cannabinoid receptors and provide
desirable
pharmacological properties without the undesirable properties associated with
increased
concentrations of cannabinoids.
[00661 The present disclosure provides novel chemical compounds of Formula
(I),
R-X-Y, that inhibit MGL or that jointly inhibit both FAAH and MGL, wherein Y
is selected
from the group consisting of:
O
-S02Y1 Y2 Y5
Y3 Y4 Y6 Y7
Il 111 IV
O
~/Y8 /Ys N \ W
1i
O Q1-Y13
V VI
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WO 2009/052320 PCT/US2008/080215
O 3 4
2 5
N Y13 FN\ Y13
Q 2 V
2 W2
and 7
vii vnl
wherein: Yj is -F, -Cl, -0-alkyl, -0-cycloalkyl, -O-heterocyclic, -0-aryl,
-0-heteroaryl, or -O-adamantyl;
Y2 is -H, -OH, -NH2, -OMe, -OEt, -CF3, -C=CH, -CH2-C=CH, -CH=CH2,
fluoroalkyl, -C1_5-alkyl, -aryl, -alkyl-aryl, -aryl-alkyl, -aryl-alkyl-Y14, -
aryl-heteroaryl,
-aryl-aryl, -heteroaryl, -heteroaryl-alkyl, -heteroaryl-alkyl-Y14, -heteroaryl-
aryl,
-heteroaryl-heteroaryl, -cycloalkyl, -cycloalkyl-alkyl, -cycloalkyl-alkyl-Y14,
-heterocyclic, -heterocyclic-alkyl, -heterocyclic-alkyl-Y14, -adamantyl,
-C1_5-alkyl-Y14, -aryl-Y14, -heteroaryl-Y14, -cycloalkyl-Y14, -heterocyclic-
Y14, or
-adamantyl-Y14;
Y3 and Y4 are each independently -F, -Cl, or -OH; or Y3 and Y4 taken
together form a ketone;
Y5 is -F, -CONH2, -SO7NH2 COON COOMe, -COOEt, CF;, -C=
-CH22-C=CH, -CH=CH2, fluoroalkyl, -C1.3-alkyl, aryl, heteroaryl, cycloalkyl,
heterocyclic, adamantyl, -C1_5-alkyl-Y14, -aryl-Y14, -heteroaryl-Y14, -
cycloalkyl-Y14,
-adamantyl-Y14, or -heterocyclic-Y14;
Y6 and Y7 are each independently -F, -Cl, or -OH;
Y8 is NH, 0, or heterocycle;
Y9 is -OY10, -N(Y11)Y12, or heterocycle;
Y10 is alkyl, aryl, benzyl, difluorophenyl, fluorophenyl, heteroaryl,
cycloalkyl,
adamantyl, heterocyclic, -C1.5-alkyl-Y14, -aryl-Y14, -heteroaryl-Y14, -
cycloalkyl-Y14.
-adamantyl-Y14, or -heterocyclic-Y14;
Y11 is -H, -alkyl, -aryl, or -alkyl-aryl;
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Y12 is alkyl, aryl, heteroaryl, cycloalkyl, adamantyl, heterocyclic,
-CI-S-alkyl-Y14, -Ci-s-alkyl-aryl, -C1.5-alkyl-heteroaryl, -aryl-(Y14)1.4,
-heteroaryl-Y14, -cycloalkyl-Y 14, -adamantyl-Y14, or -heterocyclic-Y14; or
Y11 and Y12
when taken together along with the N to which they are bonded form a 5- or
6-membered saturated heterocylic ring, the ring containing up to one
additional
heteroatom selected from the group consisting of N, 0, and S;
Y13 is -H, -OH, -SH, -NH2, -CN, -N3, -NCS, -NCO, -CONH2, -SO2NH2,
-COOH, -COOMe, -COOEt, -NO2, -CF3, -SO3H, -P(O)(OH)2, -C=CH, -CH2-C=CH,
-CH=CH2, fluoroalkyl, -C1_6-alkyl, aryl, heteroaryl, cycloalkyl, adamantyl,
heterocyclic, -C1_6-alkyl-Y14, -aryl-Y14, -heteroaryl-Y14, -cycloalkyl-Y14,
-adamantyl-Y14, or -heterocyclic-Ylo;
Y14 is -H, -F, -Cl, Br, -I, -OH, -OMe, -OEt, -OPh, -OBn, -SH, -NH2, -CN,
-N3, -NCS, -NCO, -CONH2, -SO2NH2, -COON, -COOMe, -COOEt, -NO2, -alkyl,
-CF3, -SO3H, -P(O)(OH)2, -C=CH, -CH2-C=CH, -CH=CH), or -NHCOCH3, or
-CH2OH;
W1 is CH or N if Y13 is not bonded to W1, or WI is C if Y13 is bonded to W1;
W2 is CH or N if W2 is not bonded to Y13 , or W2 is C if W is bonded to Y13;
if W2 is N then it can occupy position 4, 5, 6, or 7 in VIII;
QI is -CH2, -0, -S, or -NH if Q1 is not bonded to Y13; QI is -CH or -N if Q1
is
bonded to Y13;
Q2 is -SO2, -C(O), or -S(O);
wherein: X is -(CH2)õ-, -(CH2) -A- (CH2)1k-, cycloalkyl, or heterocycle; A is
-CH=CH-, -C=C-, C=O, 0, S, or NH; n is an integer from 0 to 15; j is an
integer from 0 to 10;
and k is an integer from 0 to 10; and wherein: R is selected from the group
consisting of.
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CA 02702950 2010-04-16
WO 2009/052320 PCT/US2008/080215
4
R~ 5 4
R,W
6l~ 5\/ 2
~ /Q3
R2 W3 2 R2 1
Ix x
4 R, 4 3
,W4
W3
R, yr
7\ 5~~ ` 2 IT R2 /J R2
7 % 2 6 Q3
W4 W3 7
8 1
xi xii
4 R,
W
4
Ri `3 5
2 R2 B
6
R2 3
1 7
XIII xIV
N -N
IN
N
Rj R,
XV XVI
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WO 2009/052320 PCT/US2008/080215
7 g 1 2
R6 W6 W5
11 ~ \ 3
R7 Rs R5
9 5 4 s
R8 R4 R1 o Alkyl
XVII and XVIII
wherein: W3 is CH, 0, or N if W3 is not bonded to X or R, or R2; W3 is
C if W3 is bonded to X or RI or R2; if W3 is N then it can occupy position 1,
2,
3, 4, 5 or 6 in IX, position 2, 3, 4 or 5 in X, position 1, 2, 3 or 4 in XI,
position
2 or 3 in XII, and position 2 or 3 in XIII;
W4 is CH or N if W4 is not bonded to X or RI or R2; W4 is C if W4 is
bonded to X or RI or R2; if W4 is N then it can occupy position 5, 6, 7 or 8
in
XI, position 4, 5, 6 or 7 in XII and position 4, 5, 6 or 7 in XIII;
W5 is CH or N if W5 is not bonded to X or R4 or R5; W5 is C if W5 is
bonded to X or R4 or R5; if W5 is N then it can occupy position 1, 2, 3, 4 or
5
in XVII;
W6 is CH or N if W6 is not bonded to R6 or R7 or R8 or R9; W6 is C if
W6 is bonded to R6 or R7 or Rs or R9; if W6 is N then it can occupy position
7,
8, 9, 10 or 11 in XVII;
Q3 is CH7, 0, S or NH if Q3 is not bonded to X or RI or R2; Q3 is CH
or N if Q3 is bonded to X or R1 or R2;
B is adamantyl or heteroadalnantyl;
R1 and R2 are each independently -H, -F, -Cl, -Br, -I, -OH, -SH, -NH2,
-CN, -N3, -NCS, -NCO, -CONH2, -SO7NH7, -COOH, -NO2, -CHO, -CF3,
-SO3H, -SO2C1, -SO2F, -O-P(O)(OH)2, -O-P(O)(O-alkyl)2,
-O-P(O)(OH)(O-alkyl), -P(O)(O-alkyl),, -P(O)(OH)(O-alkyl), -Sn(alkyl)3,
-Si(alkyl)3, -C=CH, -CH2-C=CH, -CH=CH2, -alkyl-R3, -cycloalkyl-R3,
-heterocyclic-R3. -aryl-R3, -heteroaryl-R3, -alkyl-cycloalkyl-R3,
-alkyl-heterocyclic-R3, -alkyl-aryl-R3, -alkyl-heteroaryl-R3, -Z-alkyl-R3,
26
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WO 2009/052320 PCT/US2008/080215
-Z-cycloalkyl-R3, -Z-heterocyclic-R3, -Z-aryl-R3, -Z-heteroaryl-R3,
-Z-alkyl-cycloalkyl-R3, -Z-alkyl-heterocyclic-R3, -Z-alkyl-aryl-R3,
-Z-alkyl-heteroaryl-R3, -aryl-Z-alkyl-R3, -aryl-Z-cycloalkyl-R3,
-aryl-Z-heterocyclic-R3, -aryl-Z-aryl-R3, -aryl-Z-heteroaryl-R3,
-aryl-Z-alkyl-cycloalkyl-R3, -aryl-Z-alkyl-heterocyclic-R3,
-aryl-Z-alkyl-aryl-R3, -aryl-Z-alkyl-heteroaryl-R3, -CH(alkyl-R3)2,
-C(alkyl-R3)3, -N(alkyl-R3)2, -C(O)N(alkyl-R3)2, -SO2N(alkyl-R3)2, or
adamantyl;
Z is -0, -S, -NH, -C(O), -C(O)O, -OC(O), -C(O)NH, -NHC(O), -SO,
-SO2, -SO2NH, -NHSO2, -SO2O or -OSO2;
R3 is -H, -F, -Cl, -Br, -I, -Me, -Et, -OH, -OAc, -SH, -NH2, -CN, -N3,
-NCS, -NCO, -CONH2, -SO2NH2, -COON, -NO2, -CHO, -CF3, -SO3H, -SO2F,
-O-P(O)(OH)2, -Sn(alkyl)3, -Si(alkyl)3, -OSi(alkyl)3, -C=CH, -CH2-C=CH, or
-CH=CH2;
R4, R5, R6, R7, R8, and R9 are each independently -H, -F, -Cl, -Br, -I,
-OH, -OMe, -OEt, -OCH2OCH3, -OAc, -SH, -SMe, -SEt, -NH2, -CN, -N3,
-NCS, -NCO, -CONH2, -SO2NH2, -COOH, -NO7, -CHO, -CF3, -SO3H, -SO2F,
-O-P(O)(OH)2, -Sn(alkyl)3, -Si(alkyl)3, -OSi(alkyl)3, -alkyl, or -alkyl-R3;
and
Rio is -H, -F, -Cl, -Br, -I, -OH, -OMe, -OEt, -OAc, -SH, -SMe, -SEt,
-NH2, -CN, -N3, -NCS, -NCO, -CONH2, -SO2NH2, -COOH, -NO-7, -CHO,
-CF3, -SO3H, -SO2F, -O-P(O)(OH)2, -Sn(alkyl)3, -Si(alkyl)3, -OSi(alkyl)3,
-C=CH, -CH2-C=CH or -CH=CH2; and
wherein: if Y is V, Y8 is 0 or NH, Y9 is OY10 where Y10 is alkyl, cycloalkyl,
heterocyclic, aryl, phenyl, or heteroaryl, and X is -(CH2)n- where n = 0, then
R can not be IX,
X, XI, XII, XIII, or XVIII when one of R1 or R2 is H;
if Y is V, Y8 is 0 or NH, Y9 is OY10 where Y10 is alkyl, cycloalkyl,
heterocyclic, aryl,
phenyl, or heteroaryl, and X is -(CH2)n- where n = 0-3, and R is XVII, then
each of R4, R5,
R6, R7, R8, and R9 can not be H, alkyl, OMe, OEt, F, Cl, Br, I, CN, OH, NO2,
NH2, SH, SMe,
SEt, CONH2, or SO2NH2;
27
CA 02702950 2010-04-16
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if Y is V, Y8 is 0 or NH, Y9 is N(Y11)Y12 where YI I is H and Y12 is alkyl,
cycloalkyl,
heterocyclic, aryl phenyl, or heteroaryl, or where Y11 and Y12 when taken
together along
with the N to which they are bonded form a 5- or 6-membered saturated
heterocylic ring, X is
-(CH2)n where n = 0; then R can not be IX X,
XI, XII, XIII, or XVIII when one of RI or
R2 is H; and
if Y is V, Ys is 0 or NH, Y9 is N(Y11)Y12 where Y11 is H and Y12 is alkyl,
cycloalkyl,
heterocyclic, aryl, phenyl, or heteroaryl, or where Y11 and Y12 when taken
together along
with the N to which they are bonded form a 5- or 6-membered saturated
heterocylic ring, X is
-(CH2)n- where n = 0-3, and R is XVII; then each of R4, R5, R6, R7, R8, and R9
can not be H,
alkyl, OMe, OEt, F, Cl, Br, I, CN, OH, NO2, NH2, SH, SMe, SEt, CONH2, or
SO2NH2.
[0067] The compounds of Formula (I) can also form salts which are also within
the scope
of this disclosure. Reference to a compound of the present disclosure is
understood to
include reference to salts thereof, unless otherwise indicated. The compounds
of Formula (I)
may form pharmaceutically acceptable (i.e., non-toxic, physiologically
acceptable) salts as
well as other salts that are also useful, e.g., in isolation or purification
steps which can be
employed during preparation.
[0068] The compounds of Formula (1) which contain a basic moiety, such as, but
not
limited to, an amine or a pyridine or imidazole ring, can form salts with a
variety of organic
and inorganic acids. Exemplary acid addition salts include, but are not
limited to, acetates
(such as those formed with acetic acid or trihaloacetic acid, for example,
trifluoroacetic acid),
adipates, alginates, ascorbates, aspartates, benzoates, benzenesulfonates,
bisulfates, borates,
butyrates, citrates, camphorates, camphorsulfonates, cyclopentanepropionates,
digluconates,
dodecylsulfates, ethanesulfonates, fumarates, glucoheptanoates,
glycerophosphates,
hemisulfates, heptanoates, hexanoates, hydrochlorides, hydrobromides,
hydroiodides,
hydroxyethanesulfonates (e.g., 2-hydroxyethanesulfonates), lactates, maleates,
methanesulfonates, naphthalenesulfonates (e.g., 2-naphthalenesulfonates),
nicotinates,
nitrates, oxalates, pectinates, persulfates, phenylpropionates (e.g., 3-
phenylpropionates),
phosphates, picrates, pivalates, propionates, salicylates, succinates,
sulfates (such as those
formed with sulfuric acid), sulfonates, tartrates, thiocyanates,
toluenesulfonates such as
tosylates, undecanoates, and the like.
[0069] The compounds of Formula (I) which contain an acidic moiety, such as,
but not
limited to, a carboxylic acid, can form salts with a variety of organic and
inorganic bases.
28
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Exemplary basic salts include, but are not limited to, ammonium salts, alkali
metal salts such
as sodium, lithium and potassium salts, alkaline earth metal salts such as
calcium and
nab lesium salts, salts with organic bases (for example, organic amines) such
as benzathines,
dicyclohexylamines, hydrabamines (formed with NN-bis(dehydroabietyl) ethyl
enedi amine),
N-methyl-D-glucamides, N-methyl-D-glycamides, t-butyl amines, and salts with
amino acids
such as arginine, lysine and the like. Basic nitrogen-containing groups can be
quaternized
with agents such as lower alkyl halides (e.g., methyl, ethyl, propyl, and
butyl chlorides,
bromides and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, dibutyl, and
diamyl sulfates),
long chain halides (e.g., decyl, lauryl, myristyl and stearyl chlorides,
bromides and iodides),
aralkyl halides (e.g., benzyl and phenethyl bromides), and the like.
[0070] The compounds of the present disclosure can have unnatural ratios of
atomic
isotopes at one or more of their atoms. For example, the compounds can be
labeled with
isotopes, such as deuterium, tritium carbon-11, carbon-14, iodine-123, iodine-
125 or fluorine-
18. The present disclosure encompasses all isotopic variations of the
described compounds,
whether radioactive or not.
[0071] Exemplary nonlimiting compounds of Formula (I) are listed in Tables 1
and 2
below. Solvates of the compounds of this disclosure, including hydrates of the
compounds,
as well as mixtures of the hydrate- and the keto-form of the compounds, are
within the scope
of this disclosure.
[0072]
Table 1: MGL Inhibitors of Formula (I) (R-X-Y)
Compound Structure % Inhibition IC--'0 K,
number (Concentration) ( M) (gM)
13.1* BnO \ (CH2)7-SO2F 30% 57.1 18.6
(100 M)
13.2* (CH2)7-SO2F 30%
BnO (100 M)
13.3 Q_(0H2)7-SO2F 92% 2.70 0.77
OBn (100 M)
29
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Table 1: MGL Inhibitors of Formula (I) (R-X-Y)
Compound Structure % Inhibition IC50 K;
number (Concentration) ( M) ( M)
13.4* Bno \ (CH2)5-SO2F 57% 40 15
(100 M)
14.1 * HO \ (CH2)7-SO2F 87% 98.2 32
(100 M)
14.2* Q__cH27SO2F 98% 43.7 14.3
HO (100 M)
14.3 * Q_0H2)7-SO2F 97% 43.1 14.1
OH (100 M)
14.4* HO \ (CH2)5-SO2F 56% 88.2 28.8
(100 M)
17* Q_O-(CH2)4-SO2F 26% 915 298
(100 M)
23.1 * Bno \ 0-(CH2)3-000F3 65% 103 28
(100 M)
23.2* BnO \ O-(CH2)4-000F3 64% 86.2 23.7
(100 M)
23.3Bno O-(CH2)5-000F3 61% 109 30
(100 M)
34%
23.4* Bno F\ O-(CH2)g-000F3
(100 M)
23.5* O-(CH2)3-000F3 69% 51.6 14.2
BnO (100 M)
CA 02702950 2010-04-16
WO 2009/052320 PCT/US2008/080215
Table 1: MGL Inhibitors of Formula (I) (R-X-Y)
Compound Structure % Inhibition IC50 K;
number (Concentration) (,M) ( M)
23.6* Q_O_CH2)4COCF3 66% 83.4 23.8
BnO (100 M)
23.7* r~\ O-(CH2)5 COCF3 38% 329 66.7
BnO (100 M)
23.8* QO_(CH2)3COCF3 20%
OBn (100 M)
23.9* QO_(CH2)4COCF3 47%
OBn (100 M)
23.10` Q_O_(CH2)5-000F3 66% 32.7 9.0
OBn (100 M)
23.11 * &O(CH2)3000F3 13%
23.12' Q_O_(CH2)4COCF3 %
(100 PM)
24.1 * HO -O O-(CH2)3-000F3 6%
(100 M)
24.2* Ho o-(CH2)4 COCF3 21%
(100 'UM)
24.3* HO O-(CH2)5-000F3 17%
(100 lM)
24.4* HO \ O-(CH2)6-000F3 42% 130 26.4
(100 M)
31
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Table 1: MGL Inhibitors of Formula (I) (R-X-Y)
Compound Structure % Inhibition IC50 K;
number (Concentration) ( M) ( M)
24.5* 0-(CH2)3 C CF3 3%
HO OH
HO (100 M)
24.6* O-(CH2)4 COCF3 9%
HO (100 M)
24.8* QO_(CH2)3COCF3 4%
OH (100 M)
24.10* Q_O_(CH2)5COcF3 19%
OH (100 }.iM)
27.1/ \ (CH2)3-000F3 5%
(100 M)
27.2* Q_(CH2)4-000F3 21%
(100 M)
27.3* Q_(0H2)5-cocF3 36%
(100 um)
27.4* MeO \ (CH2)4 COCF3 13%
(100 M)
30* 36% 433 109
BnO CF3
(100 M)
35* ~ 0 21%
Bn0 CF3
(100 M)
32
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Table 1: MGL Inhibitors of Formula (I) (R-X-Y)
Compound Structure % Inhibition IC50 K;
number (Concentration) ( M) ( M)
40.1 * 0 85% 36 9
F3C OH
(100 M)
HO DMH
40.3* 0 81%
F3C OMe
C6H13 (100 M)
HO
46.3* 0 35%
(100 M)
0
6
46.4* 0 sI-1 24%
NN
(100 M)
0
5%
48.7* H nJ
Ny N Br
Br 0 (100 M)
48.8* H j 32%
\ NY0 p
0 (100 M)
Br, 53.3X 0 44%
oNH (100 M)
\ Br
33
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Table 1: MGL Inhibitors of Formula (I) (R-X-Y)
Compound Structure % Inhibition IC50 Ki
number (Concentration) ( M) (tM)
53.7Y 0 34%
o)~ NH (100 M)
CH3
H3C CH3
53.8* O 54%
o NH (100 M)
P-1
CF3
53.11* 0 89%
o'J~ NH (100 M)
XC1_______
C1
53.12* O 17%
ONH (100 M)
53.13* O 76%
CANH (100 UM)
\ 53.19* Br 78%
(100 M)
CH3
H3C NH
O
0
34
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Table 1: MGL Inhibitors of Formula (I) (R-X-Y)
Compound Structure % Inhibition IC50 K;
number (Concentration) ( M) ( M)
53.23*
b~o 0 22%
H O (100 M)
O~
53.27* 0 88%
b~-O NH (100 M)
53.29* ~aOANH 0 84%
(100 M)
CI
CI
53.30* 0 72%
b~-ONH (100 M)
CI CI
53.31 * 0 54%
bLoNH (100 M)
F \ F
CA 02702950 2010-04-16
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Table l: MGL Inhibitors of Formula (I) (R-X-Y)
Compound Structure % Inhibition IC50 K;
number (Concentration) ( M) ( M)
53.32* ~a 0 18%
OANH (100 M)
O
53.33* O 21%
ONH (100 PM)
MeO OMe
OMe
53.357 O 78%
~aOANH (100 M)
53.36* o 12%
b~-O NH
(100 jiM)
SCH3
53.37* a 61%
ONH (100 M)
CI
.36
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Table 1: MGL Inhibitors of Formula (I) (R-X-Y)
Compound Structure % Inhibition IC50 Ki
number (Concentration) ( M) ( M)
53.45* 0 13%
O N (100 M)
53.46* 0 14%
bLo N (100 PM)
53.47* 0 22%
o)~ N (100 M)
I~
65.1 Jj N.N 6%
66
OA, (100 M)
74.2* 0 N, 29%
N
HO O
O~oBn (100 M)
83.2* 0
Q 2%
04N ;5.-0 (100 M)
O
83.3 * 0 1 %
0 N',s\ (100 M)
/~~ 0 0
BnO
a The group BnO- is Ph-CH,-O- where Ph is Phenyl.
b The group DMH is as shown on Scheme S.
Novel compounds.
37
CA 02702950 2010-04-16
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Table 2: MGL Inhibitors of Formula (I) (R-X-Y)
Compound Structure % Inhibition IC50 K1
number (Concentration)
4.1 Q_CH23-SO2F I nM
- 100
M
4.2* D-(CH2)7-SO2F I nM
- 100
M
4.3' Q-_CH28-SO2F 1 nM
-100
M
x InM
18 BnO D \ (CH2)7-SO2OMe - 100
M
24.7* /\O-(CH2)5-000F3 1 nM
- 100
HO M
24.9* QO_(CH2)4COCF3 1 nM
100
OH M
39.1b 0 1 nM
\ - 100
F3C OMe M
e DMH
39.2 o I nM
1 - 100
F3C \ I OMe m
~
MeO I C5H11
39.3* 0 1 nM
1 -100
F3C OMe um
C6H13
Me0
39.4 0 1 nM
-100
F3C Cl OMe uM
OMe
38
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Table 2: MGL Inhibitors of Formula (I) (R-X-Y)
Compound Structure % Inhibition IC50 Ki
number (Concentration)
46.1 * HO 1 nM
I o N_< -100
4~ M
0
46.2* HO 1 nM
O N-O - 100
4 o M
46.5* HO 1 nM
O N -100
4~ M
0
48.1 H 98%
y -
Br (100 um)
48.2 -1-0 H 44%
N
Br (100 PM)
48.3 H 92%
Oy
O (100 M)
Br
48.4 0 H 99% 15.4 3.9
-O Br / Br (100 M) 1iM M
48.5* 1 nM
-100
OCN8r O H
y uM
F 48
.6 \ pYH 52%
I a[ (100 M)
48.9 H 29%
Ny0 O
Br 0 (100 M)
39
CA 02702950 2010-04-16
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Table 2: MGL Inhibitors of Formula (I) (R-X-Y)
Compound Structure % Inhibition IC50 K;
number (Concentration)
H 1 nM
52.1 O
y N OCH2OCH3 - 100
0 }.1M
CH3O CH2O DMH
52.2 ~o H 92%
OCH2OCH3
o (100 M)
CH3OCH2O DMH
52.3 H 96%
OCH2OCH3
(100 M)
CH3OCH2O DMH
H 1 nM
52.4 O i N OCH2OCH3 - 100
M
CH3OCH2O DMH
53.1 Cr00yN H OH 41%
~ I
(100 M)
HO DMH
53.2 ~o H \ ( OH 63%
o
(100 M)
HO DMH
53.4x 1 nM
-100
O-J~NH (.gym
I
OMe
53.5 ~ft 0 88%
o)~NH (100 um)
0
NO2
CA 02702950 2010-04-16
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Table 2: MGL Inhibitors of Formula (I) (R-X-Y)
Compound Structure % Inhibition IC50 K,
number (Concentration)
53.6* 1 nM
-100
O'kNH tM
0
NO2
53.10* 1 100
- 100
~ NH p,M
OH
53.14* 1nM
-100
O~NH M
H;C
\ I CH;
OH
53.15* 1 nM
-100
O NH M
CH,
H3C
OH
53.16* 1 nM
-100
ONH M
OH
53.17* 1 nM
- 100
oL~ N M
53.18* 1 nM
-100
O)~ NH M
HN r O
41
CA 02702950 2010-04-16
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Table 2: MGL Inhibitors of Formula (I) (R-X-Y)
Compound Structure IN, Inhibition IC50 K;
number (Concentration)
53.15* 1 nM
-100
ONH uM
/ CH3 r
H,C
OH
53.20* CH3 1 nM
H3C H - 100
oy M
off
53.21* 1 nM
-100
}tM
0 N
53.22* 1 nM
-100
bLo H 0
53.9' 1 nM
- 100
O~ NH M
I
OH
53.24* 0 1 nM
N' -100
ON M
H
53.25* 1 nM
H;C H - 100
oy N M
off
53.26* 1 nM
-100
b---O NH ~ Lm
Br
42
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Table 2: MGL Inhibitors of Formula (I) (R-X-Y)
Compound Structure % Inhibition IC50 K;
number (Concentration)
53.28X 1 nM
-100
oNH uM
CN
53.34X 1 nM
-100
ONH ~tM
O
53.38* 1 nM
C1 -100
M
b-0-c~-)-
53.39* 1 nM b--O-O ` N~-oH -100
M
53.40* OH 1 nM
- 100
\N M
53.41 Y 1 nM
- 100
b--ao N~(_j M
O
53.42* HO 1 nM
- 100
_ o\ M
O N
b--
53.43X 1 nM
-100
M
43
CA 02702950 2010-04-16
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Table 2: MGL Inhibitors of Formula (I) (R-X-Y)
Compound Structure % Inhibition IC50 K,
number (Concentration)
53.44 1 nM
o a -100
bLo)'O'
53.48 H 70%
N / OH
0 (100 M)
HO DMH
53.49 0yN \ OH 50%
(100 M)
HO DMH
57.1 0 44%
,--- a,--
H Br (100 M)
57.2 0 92%
Br (100 M)
57.3* A \ 1 1 0
N o M
57.4* A 1 nM N O \ NMe2 -10
M
57.SX 0 1 nM
~ I -100
N O \ CN M
59.1 N_ 1 nM
(CH2)3 NH C NH CH2 / -100
O
M
59.2* N 1 nM
(CH2)3-NH-C-NH - 100
0 uM
59.3Y H I nM
NON - 100
o M
0
44
CA 02702950 2010-04-16
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Table 2: MGL Inhibitors of Formula (I) (R-X-Y)
Compound Structure % Inhibition IC50 K,
number (Concentration)
59.4* NON 1 nM
- 100
uM
o
59.5 p 1 nM
-100
PhN N um
59.6 ON 1 nM
- 100
Ph~NAN
H
59.7 o oN -100
Ph -N ~rN
~ H ltM
65.2* 0 1 nM
N,N -100
s O! M
BnO :
66* o 1 nM
I \ o-~ 100
6
o M
HO
73.*1 0 1 nM
0JNN - 100
O_'"~OBn M
73.2* O 1 nM
Bn0 5 N N - 100
OI__~IOBn tM
74.1 * 0 1 nM
~N N -100
/ \ o M
OOH
78* 1 nM
N -100
BnO \ \ r N
o- M
81* 0 1 nM
Me0 N - 100
I O_K
CA 02702950 2010-04-16
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Table 2: MGL Inhibitors of Formula (I) (R-X-Y)
Compound Structure % Inhibition IC50 K,
number (Concentration)
1nM
81.1X N~ -100
o M
0
83.1 * 0 1 nM
- 100
83.4* o 1 nM
-100
0 No 0 M
83.5 * 0 - 1 nM
- 100
0N /\O M
O
83.6* O 1 nM
-100
Me\ 04N,S\ M
83.7* 0 1 nM
-100
M
O
C1 = ~aN =
C11
83.8* o 1 nM
-100
S,o 6N o \0- M
83.9* O - 1 nM
- 100
O2N O N S M
O \O
84* O 1 nM
O N,~ -100
\ 4 p M
HO
46
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Table 2: MGL Inhibitors of Formula (1) (R-X-Y)
Compound Structure % Inhibition IC-50 K;
number (Concentration)
84.17 1 nM
~/o -100
S\NH tM
0
84.2* O o 1 nM
S -100
NH tm
O
OCH2Ph
84.3* 0 1 nM
-100
NH M
S O
0
84.4* 0 1 nM
-100
M
00104NH
o
84.5* 1 nM
~/O -100
S\N H ~LM
0
84.6* 9,O 1 nM
-100
NH M
O
OH
84.7* 1 nM
,O -100
S
,NH M
O
CN
47
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Table 2: MGL Inhibitors of Formula (I) (R-X-Y)
Compound Structure % Inhibition IC50 K;
number (Concentration)
84.8* ~s 1 nM
,'O -100
NH M
0
CI CI
84.9* 1 nM
O~Sz -100
NH M
Si O
84.10* O O 1 nM
SNH -100
M
0
0 CH3
84.11* 1 nM
O\ S0 -100
NH M
0
F3C CI
84.12* 1 nM
O'S/ -100
\ NH M
0
I
H3CO CI
84.13* 1 nM
OS0 -100
H C NH }LM
3
O
CI
84.14* O 1 nM
'S/ -100
NH M
F3C
0
CI
48
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Table 2: MGL Inhibitors of Formula (I) (R-X-Y)
Compound Structure % Inhibition IC50 Ki
number (Concentration)
84.15* OSo 1 nM
-100
NH M
F3CO
0
CI
84.16* 0/ 1 nM
-100
O NH M
H3C
I , O
CI
84.17* 0So 1 -100
NH M
0
OCH3
OCH3
84.18* O O 1 nM
- 100
S
NH M
0
H3CO OCH3
84.19* 1 nM
OS~ -100
H3CO I , NH }tM
0
OCH3
84.207 OIS1 1 nM
- 100
OCH3I NH M
0
OCH3
87.1 0 82%
OEt
0 (100 M)
BnO
87.2 0 1 nM
OEt - 100
0 M
49
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Table 2: MGL Inhibitors of Formula (I) (R-X-Y)
Compound Structure % Inhibition IC50 K;
number (Concentration)
87.3 0 1 nM
---~. OEt -100
Bn0 0
0 M
87.4 0 66%
/ 0 (100 M)
87.7 0 1 nM
oEt -100
0 M
89.1 F FMe 17.9 4.5
/ \ o
0 M uM
BnO
89.2 F F 1nM
//--\\\--o Me - 100
0 M
89.4 DO\NN(CH3 72%
0 (100 M)
89.7 0 0.071 0.017
F F o- ItM M
89.8 FF 55%
/ \ 0 Me
o (100 M)
89.9 F F 59% 0.99 0.25
0-0----- M M
o (100 M)
89.9 F N 69%
Hydrate HO OH (100 M)
form
89.10 F F N 25%
0 (100 M)
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Table 2: MGL Inhibitors of Formula (I) (R-X-Y)
Compound Structure % Inhibition IC50 K;
number (Concentration)
89.11 FF NII 65%
0 (100 M)
BnO
89.12 F -N 73% 0.215 0.054
/ \ 0 0 M M
o (100 M)
0.072
89.13 F. F N-N\-
o M
BnO
89.14 F F N 1 nM
-100
/ \ o 1 M
0
BnO
89.15* 0 1 nM
---- ~ Q - 100
F OCH,Ph O M
\-0
89.16' ,',"x y 1 100
91 F F O~(M
OCH2Ph OTBDMS
91.1 0 51.6 12.9
OEt M M
0
0 23%
91.2 Q0Et
0 (100 M)
91.3 0 1 nM
-100
O Et
M
0
91.4 0 1 nM
OEt - 100
M
%0
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Table 2: MGL Inhibitors of Formula (I) (R-X-Y)
Compound Structure % Inhibition IC50 K;
number (Concentration)
91.5 0 79%
Br-(:Y~-OEt
0 (100 M)
91.6 Q-OEt 1M
-100
Me O M
93.1 F F N,.N 50% 0.34 0.086
r \`
o (100 M) M M
93.2 F F N 1 nM
- 100
0 0 M
93.5 / F F NON 97% 1.69 0.42
Br _ r õ
0 0 (100 M) M M
93.7 F F 91%
0 Br (100 M)
N
93.8 F F N 32%
o s (100 M)
93.9 1 nM
F F - 100
\ M
0
96.1 \ 0 11 11 76%
N
F F (100 M)
96.2 o n
11 86%
F F N (100 M)
'The group BnO- is Ph-CH,)-O- where Ph is Phenyl.
b The group DMH is as shown on Scheme 8.
* Novel compounds.
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[0073] The inhibitory compounds can be synthesized by chemical means as
described in
the Examples below. Some inhibitory compounds may be commercially available.
Novel
compounds may be synthesized from commercially available starting material.
The
inhibitory compounds need not be made exclusively from the illustrative
syntheses. A person
of skill in the art understands that additional methods of making the
inhibitory compounds
exist. A person of skill in the art also understands that general synthetic
schemes for the
compounds disclosed herein can be understood from the illustrative schemes
below.
3. Methods of Inhibition and Modulation
[0074] This disclosure is also directed to a method of modulating cannabinoid
receptors
in a biological sample by using the compounds of Formula (I), and
pharmaceutically
acceptable salts thereof. The method comprises (a) measuring the level of a
cannabinergic
ligand in the biological sample, (b) contacting the sample with a compound of
Formula (1),
thereby inhibiting an enzyme that hydrolyzes the cannabinergic ligand, and (c)
measuring the
level of the cannabinergic ligand in the contacted sample, the cannabinoid
receptors being
modulated if the level of the cannabinergic ligand in the contacted sample is
the same or
greater than the level of the cannabinergic ligand in the uncontacted sample.
[0075] In some instances, the enzyme inhibited is MGL. Testing of some
compounds of
Formula (I) shows inhibition of MGL in both in vitro and in vivo systems.
Inhibition of MGL
has the effect of preventing the degradation of endocannabinoid ligands and
increasing or
maintaining the level of endocannabinoid ligands in a system. Thus, the
disclosed
compounds, when administered in a therapeutically effective amount, increase
or maintain
the in vivo concentration of endogenous cannabinergic ligands in a subject,
thereby
enhancing or maintaining activation of cannabinoid receptors. In other
instances, the
inhibitor also inhibits FAAH in addition to MGL. The joint inactivation of
both enzymes
leads to enhanced therapeutic benefits because cannabinoid receptors can be
modulated by
additional cannabinergic ligands.
4. Methods of Treatment Using MGL Inhibitory Compounds
Disorders
[0076] Some of the physiological effects provided by modulation of the
cannabinoid
receptors by cannabinergic ligands are useful to treat a disorder in a
subject. Such treatable
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physiological effects include, but are not limited to, neuroprotection;
reduction of
inflammation; reduction of pain; reduction of central pain; reduction of
peripheral pain;
modulation of memory; sleep inducement; modulation of the immune system;
hypotension;
reduction of emesis; effects on gastrointestinal motility; effects on motor
function; effects on
intestinal transit and colonic propulsion; modulation of appetite; and
modulation of fertility.
Inhibition of MGL activity increases or maintains the concentration of
existing levels of
endogenous cannabinergic ligands and thereby increases or maintains the
magnitude and
duration of the physiological effect provided by those cannabinergic ligands.
Therefore, the
disclosed compounds, and therapeutic formulations containing such compounds,
enhance or
maintain the magnitude and duration of the physiological effects produced by a
cannabinergic
ligand in a subject when administered in therapeutically effective amounts.
100771 Disorders that can be treated by inhibition of MGL and/or MGL and FAAH
and
indirect stimulation of the cannabinoid receptors include, for example:
appetite disorders,
metabolic disorders, movement disorders, inflammation, pain, neuropathic pain
(e.g.,neuropathic low back pain, complex regional pain syndrome, post
trigeminal neuralgia,
causal(yia, toxic neuropathy, reflex sympathetic dystrophy, diabetic
neuropathy, chronic
neuropathy caused by chemotherapeutic agents), central pain, peripheral pain,
neuropathy
(e.g.,diabetic neuropathy, pellagric neuropathy, alcoholic neuropathy,
Beriberi neuropathy,
burning feet syndrome), neurodegenerative diseases including multiple
sclerosis, Parkinson's
disease, Huntington's chorea, Alzheimer's disease, amyotrophic lateral
sclerosis; memory
disorders, mood disorders, sleep disorders, gastrointestinal motility
disorders such as irritable
bowel syndrome and diarrhea; cardiovascular disease, hypertension,
osteoporosis,
osteoarthritis, emesis, epilepsy, mental disorders such as schizophrenia and
depression;
glaucoma, cachexia, insomnia, traumatic brain injury, spinal cord injury,
seizures, excitotoxin
exposure, ischemia, AIDS wasting syndrome, psychological disorders including
anxiety
disorders (e.g.,panic disorder, acute stress disorder, post-traumatic stress
disorder, substance-
induced anxiety disorders, obsessive-compulsive disorder, agoraphobia,
specific phobia,
social phobia), to modulate the immune system; to regulate fertility; to
prevent or reduce
diseases associated with motor function such as Tourette's syndrome; to
provide
neuroprotection, to produce peripheral vasodilation; to slow down intestinal
transit and
colonic propulsion; to treat several types of cancer, as well as other
ailments in which a
growing family of bioactive lipid mediators is implicated.
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[0078] The disclosed inhibitory compounds and pharmaceutical formulations can
also be
used in combination with one or more agents treating and/or targeting the
disorder or the
endogenous cannabinergic system. Such agents include, but are not limited to,
CB1
cannabinoid receptor agonists, CB2 cannabinoid receptor agonists, analgesics,
FAAH
inhibitors, anandamide transport inhibitors, COX-2 enzyme inhibitors,
anxiolytics,
antidepressants, and opioids. For example, these compounds and pharmaceutical
formulations can be used in conjunction with other cannabinergic ligands that
act directly on
the CB 1 and CB2 receptors.
10079] In certain instances, the cannabinergic ligand is 2-
arachidonoylglycerol. The
disclosed compounds have high potential to be used as research tools to probe
MGL and
related lipase mechanisms of catalysis, and to uncover the biological roles of
lipid mediators
such as 2-arachidonoylglycerol. For example, the disclosed compounds can be
used as in
vivo imaging agents; to maintain the level of 2-arachidonoylglycerol in vitro
to study the
effect of 2-arachidonoylglycerol in cells and to enhance the levels of 2-
arachidonoylglycerol
in vivo in order to study the effect of 2-arachidonoylglycerol on humans and
animals. The
disclosed compounds can be used to characterize cells, for example, to
determine if a cell
type has cannabimimetic or lipase activity. For example, the disclosed
compounds can be
used to determine if a cell population expresses MGL by contacting the cells
with a disclosed
compound and then determining if there is an increase in the concentration of
2-arachidonoylglycerol. The inhibitors disclosed in this application can also
be used as an
aid in drug design, for example as a control in assays for testing other
compounds for their
ability to inhibit MGL and to determine the structure activity requirements of
MGL
inhibitors.
[0080] The disclosed compounds can also be used to prepare prodrugs. Prodrugs
are
known to those skilled in the art of pharmaceutical chemistry, and provide
benefits such as
increased adsorption and half-life. Those skilled in the art of drug delivery
will readily
appreciate that the phannacokinetic properties of Formula (I) can be
controlled by an
appropriate choice of moieties to produce prodrug derivatives.
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Formulation
[0081] This disclosure is also directed to a pharmaceutical formulation
comprising at
least one compound of Formula (I), and a pharmaceutically-acceptable carrier.
Such
formulations are suitable for administration to a subject. The pharmaceutical
formulation can
be used for treating a disorder described above.
[0082] Any suitable pharmaceutically acceptable carrier known in the art can
be used as
long as it does not affect the inhibitory activity of a compound of Formula
(I). Carriers may
be used that efficiently solubilize the agents. Carriers include, but are not
limited to, a solid,
liquid, or a mixture of a solid and a liquid. The carriers can take the form
of capsules, tablets,
pills, powders, lozenges, suspensions, emulsions, or syrups. The carriers can
include
substances that act as flavoring agents, lubricants, solubilizers, suspending
agents, binders,
stabilizers, tablet disintegrating agents, and encapsulating materials. Other
examples of
suitable physiologically acceptable carriers are described in Remington's
Pharmaceutical
Sciences (21st ed. 2005), incorporated into this disclosure by reference.
[0083] Non-limiting examples of materials which can serve as pharmaceutically-
acceptable carriers include: (1) sugars, such as lactose, glucose, and
sucrose; (2) starches,
such as corn starch and potato starch; (3) cellulose and its derivatives, such
as sodium
carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; (4) powdered
tragacanth; (5)
malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and
suppository waxes; (9) oils,
such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn
oil, and soybean
oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin,
sorbitol, mannitol,
and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate;
(13) agar; (14)
buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15)
alginic acid;
(16) pyrogen-free water; (17) isotonic saline, (18) Ringer's solution, (19)
ethyl alcohol; (20)
phosphate buffer solutions; and (21) other non-toxic compatible substances
employed in
pharmaceutical fonmulations.
[0084] The formulations can conveniently be presented in unit dosage form and
can be
prepared by any methods known in the art of pharmacy. The amount of compound
of
Formula (I) which can be combined with a carrier material to produce a single-
dosage form
will vary depending upon the subject being treated, the particular mode of
administration, the
particular condition being treated, among others. The amount of active
ingredient that can be
combined with a carrier material to produce a single-dosage form will
generally be that
amount of the compound that produces a therapeutic effect. Generally, out of
one hundred
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percent, this amount will range from about 1 percent to about ninety-nine
percent of active
ingredient, in some instances from about 5 percent to about 70 percent, in
other instances
from about 10 percent to about 30 percent.
[00851 Methods of preparing these formulations or compositions include the
step of
bringing into association a compound disclosed in this application with a
carrier and,
optionally, one or more accessory ingredients. In general, the formulations
are prepared by
uniformly and intimately bringing into association a compound of Formula (1)
with liquid
carriers, or timely divided solid carriers, or both, and then, if necessary,
shaping the product.
[0086[ In solid dosage forms of the disclosed compounds for oral
administration (e.g.,
capsules, tablets, pills, dragees, powders, granules, and the like), the
active ingredient is
mixed with one or more additional ingredients, such as sodium citrate or
dicalcium
phosphate, and/or any of the following: (1) fillers or extenders, such as, but
not limited to,
starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2)
binders, such as, but not
limited to, carboxymethyl cellulose, alginates, gelatin, polyvinyl
pyrrolidone, sucrose, and/or
acacia; (3) humectants, such as, but not limited to, glycerol; (4)
disintegrating agents, such as,
but not limited to, agar, calcium carbonate, potato or tapioca starch, alginic
acid, certain
silicates, and sodium carbonate; (5) solution retarding agents, such as, but
not limited to,
paraffin; (6) absorption accelerators, such as, but not limited to, quaternary
ammonium
compounds; (7) wetting agents, such as, but not limited to, cetyl alcohol and
glycerol
monostearate; (8) absorbents, such as, but not limited to, kaolin and
bentonite clay; (9)
lubricants, such as, but not limited to, talc, calcium stearate, magnesium
stearate, solid
polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and (10)
coloring agents.
In the case of capsules, tablets, and pills, the pharmaceutical compositions
can also comprise
buffering agents. Solid compositions of a similar type can also be employed as
fillers in soft
and hard-filled gelatin capsules using such excipients as lactose or milk
sugars, as well as
high molecular weight polyethylene glycols, and the like.
[00871 In powders, the carrier is a finely-divided solid, which is mixed with
an effective
amount of a finely-divided agent. Powders and sprays can contain, in addition
to a
compound of Formula (1), excipients, such as lactose, talc, silicic acid,
aluminum hydroxide,
calcium silicates and polyamide powder, or mixtures of these substances.
Sprays can
additionally contain customary propellants, such as chlorofluorohydrocarbons
and volatile
unsubstituted hydrocarbons, such as butane and propane.
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[0088] Tablets for systemic oral administration can include one or more
excipients as
known in the art, such as, for example, calcium carbonate, sodium carbonate,
sugars (e.g.,
lactose, sucrose, mannitol, sorbitol), celluloses (e.g., methyl cellulose,
sodium carboxyrnethyl
cellulose), gums (e.g., arabic, tragacanth), together with one or more
disintegrating agents
(e.g., maize, starch, or alginic acid, binding agents, such as, for example,
gelatin, collagen, or
acacia), lubricating agents (e.g., magnesium stearate, stearic acid, or talc),
inert diluents,
preservatives, disintegrants (e.g., sodium starch glycolate), surface-active
and/or dispersing
agent. A tablet can be made by compression or molding, optionally with one or
more
accessory ingredients.
[0089] In solutions, suspensions, emulsions or syrups, an effective amount of
a disclosed
compound is dissolved or suspended in a carrier, such as sterile water or an
organic solvent,
such as aqueous propylene glycol. Other compositions can be made by dispersing
the agent
in an aqueous starch or sodium carboxyrmethyl cellulose solution or a suitable
oil known to
the art. The liquid dosage forms can contain inert diluents commonly used in
the art, such as,
for example, water or other solvents, solubilizing agents and emulsifiers,
such as, but not
limited to, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate,
benzyl alcohol,
benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular,
cottonseed,
groundnut, corn, germ, olive, castor and sesame oils), glycerol,
tetrahydrofuryl alcohol,
polyethylene glycols, and fatty acid esters of sorbitan, and mixtures thereof.
[0090] Besides inert diluents, the oral compositions can also include
adjuvants, such as
wetting agents, emulsifying and suspending agents, sweetening, flavoring,
coloring,
perfuming, and preservative agents.
[0091] Suspensions can contain, in addition to the active compound, suspending
agents
as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and
sorbitan esters,
mnicrocrystal line cellulose, aluminum metahydroxide, bentonite, agar and
tragacanth, and
mixtures thereof.
[0092] Formulations of the pharmaceutical compositions for rectal or vaginal
administration can be presented as a suppository, which can be prepared by
mixing one or
more compounds of this disclosure with one or more suitable non-irritating
excipients or
carriers comprising, for example, cocoa butter, polyethylene glycol, a
suppository wax or a
salicylate, and which is solid at RT but liquid at body temperature and, thus,
will melt in the
rectum or vaginal cavity and release the agents. Formulations suitable for
vaginal
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administration also include, but are not limited to, pessaries, tampons,
creams, gels, pastes,
foams, or spray formulations containing such carriers as are known in the art
to be
appropriate.
[0093] Dosage forms for the topical or transdermal administration of a
compound of this
disclosure include, but are not limited to, powders, sprays, ointments,
pastes, creams, lotions,
gels, solutions, patches, and inhalants. The active compound can be mixed
under sterile
conditions with a pharmaceutically-acceptable carrier, and with any
preservatives, buffers, or
propellants.
[0094] Ointments, pastes, creams, and gels can contain, in addition to an
active
compound, excipients, such as animal and vegetable fats, oils, waxes,
paraffins, starch,
tragacanth, cellulose derivatives, polyethylene glycols, silicones,
bentonites, silicic acid, talc
and zinc oxide, or mixtures thereof.
[0095] Transdennal patches have the added advantage of providing controlled
delivery of
a compound of Formula (I) to the body. Such dosage forms can be made by
dissolving or
dispersing the agents in the proper medium. Absorption enhancers can also be
used to
increase the flux of the agents across the skin. The rate of such flux can be
controlled by
either providing a rate controlling membrane or dispersing the compound in a
polymer matrix
or gel.
[0096] The compounds of Formula (1) are administered in a therapeutically
effective
amount to a patient in need of such treatment. Such an amount is effective in
treating a
disorder of the patient. This amount can vary, depending on the activity of
the agent utilized,
the nature of the disorder, and the health of the patient. A skilled
practitioner will appreciate
that the therapeutically-effective amount of a compound of Formula (I) can be
lowered or
increased by fine-tuning and/or by administering more than one compound of
Formula (I), or
by administering a compound of Formula (I) together with a second agent (e.g.,
antibiotics,
antifungals, antivirals, NSAIDS, DMARDS, steroids, etc.). Therapeutically-
effective
amounts can be easily determined, for example, empirically by starting at
relatively low
amounts and by step-wise increments with concurrent evaluation of beneficial
effect (e.g.,
reduction in symptoms). The actual effective amount will be established by
dose/response
assays using methods standard in the art (Johnson et al., Diabetes., (1993)
42:1179). As is
known to those in the art, the effective amount will depend on
bioavailability, bioactivity, and
biodegradability of the compound of Formula (I).
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[0097] A therapeutically-effective amount is an amount that is capable of
reducing a
symptom of a disorder in a subject. Accordingly, the amount will vary with the
subject being
treated. Administration of the compound of Formula (I) can be hourly, daily,
weekly,
monthly, yearly, or a single event. For example, the effective amount of the
compound can
comprise from about I g/kg body weight to about 100 mg/kg body weight. In one
embodiment, the effective amount of the compound comprises from about 1 ~tg/kg
body
weight to about 50 mg/kg body weight. In a further embodiment, the effective
amount of the
compound comprises from about 10 g/kg body weight to about 10 ing/kg body
weight.
When one or more compounds of Formula (I) or agents are combined with a
carrier, they can
be present in an amount of about 1 weight percent to about 99 weight percent,
the remainder
being composed of the pharmaceutically-acceptable carrier.
Administration
[0098] Methods of administration of the therapeutic formulations comprising
the
compounds of Formula (I) can be by any of a number of methods known in the
art. These
methods include, but are not limited to, local or systemic administration.
Exemplary routes
of administration include, but are not limited to, oral, parenteral,
transdermal, intradernal,
intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal (e.g.,
nebulizer, inhaler,
aerosol dispenser), colorectal, rectal, intravaginal, and any combinations
thereof. In addition,
it may be desirable to introduce pharmaceutical compositions of the disclosed
compounds
into the central nervous system by any suitable route, including
intraventricular and
intrathecal injection. Intraventricular injection can be facilitated by an
intraventricular
catheter, for example, attached to a reservoir, such as an Ommaya reservoir.
Methods of
introduction can be provided by rechargeable or biodegradable devices, e.g.,
depots.
Furthermore, administration can occur by coating a device, implant, stent, or
prosthetic. The
compounds of Formula (I) can also be used to coat catheters in any situation
where catheters
are inserted in the body.
[0099] The therapeutic formulations containing a compound of Formula (I) can
also be
administered as part of a combinatorial therapy with other agents. Combination
therapy
refers to any form of administration combining two or more different
therapeutic compounds
such that the second compound is administered while the previously
administered therapeutic
compound is still effective in the body (e.g., the two compounds are
simultaneously effective
in the patient, which may include synergistic effects of the two compounds).
For example,
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the different therapeutic compounds can be administered either in the same
formulation or in
a separate formulation, either simultaneously or sequentially. Thus, an
individual who
receives such treatment can have a combined (conjoint) effect of different
therapeutic
compounds.
[0100] In other instances, for example, in the case of inflammatory
conditions, a
therapeutic formulation containing a compound of Formula (1) can be
administered in
combination with one or more other agents useful in the treatment of
inflammatory diseases
or conditions. Agents useful in the treatment of inflammatory diseases or
conditions include,
but are not limited to, anti-inflammatory agents, or antiphlogistics.
Exemplary antiphlogistics
include, but are not limited to, glucocorticoids, such as cortisone,
hydrocortisone, prednisone,
prednisolone, fluorcortolone, triamcinolone, methyiprednisolone, prednylidene,
paramethasone, dexamethasone, betamethasone, beclomethasone, fluprednylidene,
desoxymethasone, fluocinolone, flunethasone, diflucortolone, clocortolone,
clobetasol and
fluocortin butyl ester; immunosuppressive agents such as anti-TNF agents
(e.g., etanercept,
infliximab) and IL-1 inhibitors; penicillamine; non-steroidal anti-
inflammatory drugs
(NSAIDs) which encompass anti-inflammatory, analgesic, and antipyretic drugs
such as
salicyclic acid, celecoxib, difunisal and from substituted phenylacetic acid
salts or 2-
phenylpropionic acid salts, such as alclofenac, ibutenac, ibuprofen,
clindanac, fenclorac,
ketoprofen, fenoprofen, indoprofen, fenclofenac, diclofenac, flurbiprofen,
piprofen,
naproxen, benoxaprofen, carprofen and cicloprofen; oxican derivatives, such as
piroxican;
anthranilic acid derivatives, such as mefenamic acid, flufenamic acid,
tolfenamic acid and
meclofenamic acid, anilino-substituted nicotinic acid derivatives, such as the
fenamates
miflulnic acid, clonixin and flunixin; heteroarylacetic acids wherein
heteroaryl is a 2-indol-3-
yl or pyrrol-2-yl group, such as indomethacin, oxmetacin, intrazol,
acemetazin, cinmetacin,
zomepirac, tolmetin, colpirac and tiaprofenic acid; idenylacetic acid of the
sulindac type;
analgesically active heteroaryloxyacetic acids, such as benzadac;
phenylbutazone; etodolac;
nabunetone; and disease modifying antirheumatic drugs (DMARDs) such as
methotrexate,
gold salts, hydroxychloroquine, sulfasalazine, ciclosporin, azathioprine, and
leflunomide.
Other therapeutics useful in the treatment of inflammatory diseases or
conditions include
antioxidants. Antioxidants can be natural or synthetic. Antioxidants are, for
example,
superoxide dismutase (SOD), 21-aminosteroids/aminochromans, vitamin C or E,
etc. Many
other antioxidants are known to those of skill in the art. The compounds of
Formula (I) can
serve as part of a treatment regimen for an inflammatory condition, which may
combine
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many different anti-inflammatory agents. For example, the subject compounds
can be
administered in combination with one or more of an NSAID, DMARD, or
immunosuppressant. The subject compounds can also be administered in
combination with
methotrexate. The subject antibodies can also be administered in combination
with a TNF-a
inhibitor.
[0101] In the case of cardiovascular disease conditions, and particularly
those arising
from atherosclerotic plaques, which are thought to have a substantial
inflammatory
component, the therapeutic formulation including a compound of Formula (1) can
be
administered in combination with one or more other agents useful in the
treatment of
cardiovascular diseases. Agents useful in the treatment of cardiovascular
diseases include,
but are not limited to, (3-blockers such as carvedilol, lnetoprolol,
bucindolol, bisoprolol,
atenolol, propranolol, nadolol, timolol, pindolol, and labetalol; antiplatelet
agents such as
aspirin and ticlopidine; inhibitors of angiotensin-converting enzyme (ACE)
such as captopril,
enalapril, lisinopril, benazopril, fosinopril, quinapril, ramipril, spirapril,
and moexipril; and
lipid-lowering agents such as mevastatin, lovastatin, simvastatin,
pravastatin, fluvastatin,
atorvastatin, and rosuvastatin.
[0102] In the case of cancer, the subject compounds can be administered in
combination
with one or more anti-angiogenic factors, chemotherapeutics, or as an adjuvant
to
radiotherapy. It is further envisioned that the administration of the subject
compounds will
serve as part of a cancer treatment regimen, which may combine many different
cancer
therapeutic agents.
[0103] The disclosure is further illustrated by the following examples, which
are not to be
construed as limiting this disclosure in scope or spirit to the specific
procedures described in
this disclosure. It is to be understood that the examples are provided to
illustrate certain
embodiments and that no limitation to the scope of the disclosure is intended
thereby. It is to
be further understood that resort may be had to various other embodiments,
modifications,
and equivalents thereof which may suggest themselves to those skilled in the
art without
departing from the sprint of the present disclosure and/or scope of the
appended claims.
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EXAMPLES
Testing of Inhibitory Compounds
[0104] Certain compounds were tested for their MGL inhibitory activity, which
is
expressed as % of inhibition or IC50/Ki values in Tables 1 and 2. The
percentage of
inhibition describes the percentage by which the inhibitor reduces the
velocity/rate of 2-AG
hydrolysis by MGL. The IC50 is the concentration of the inhibitor, which
results in 50%
inhibition of the velocity/rate of 2-AG hydrolysis by MGL. The K; value is the
affinity
constant and describes the affinity of the inhibitor for the MGL. The lower
the IC50/K; values,
the higher the affinity of the inhibitor for the enzyme and the higher its
inhibitory activity. A
detailed description of the methods used to test inhibitory activity of
compounds is given
below. The compounds in Table 2 are also assayed for their inhibitory activity
as described
below, and their activity or expected activity ranges are provided.
1. Partial Purification of MGL
[0105] Monoacylglycerol lipase enzyme was partially purified from adult
Sprague-
Dawley rat brains purchased from Pel-Free-ze Biologicals according to a
procedure disclosed
in Lang et al., Anal. Biochem. (1996) 238:40-45. These rat brains are
homogenized in 5
volumes of ice-cold buffer (0.32 M sucrose, 10 mM Tris base, 5 mM EDTA, pH
7.4) then
centrifuged at 17400 g for 30 min. The supernatant was further centrifuged at
124,000 g for
90 min. The supernatant from the last certifugation step (cytosol fraction) is
resuspended in
THE buffer (25 mM Tris base, 5 mM MgCl,, 1 mM EDTA, pH 7.4) for the MGL
preparation. Aliquots (I ml) from the preparation are flash frozen in liquid
nitrogen and
stored at -80 C until used. Protein concentration of the enzyme suspension is
determined
using the BioRad protein assay kit.
2. MGL Enzyme Assay
[0106] All compound solutions are made to a concentration of 10 mM in DMSO. To
test
the stability of the potentially therapeutic compounds in enzyme assay
conditions, 25 nmoles
of the compound are incubated in THE buffer (final volume of 250 L) for 20
min at 37 C.
Samples (100 L) are taken at the start of the assay and after 20 min, diluted
1:5 with
acetonitrile and centrifuged (20,000 RCF, five min, RT) to precipitate the
proteins. The
resulting supernatant is injected onto the HPLC. Calculations for determining
the percent
compound remaining are described in the following equation:
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%R = Peak Area (T20)/Peak Area (TO)
[0107] To determine whether or not the compounds are good substrates for MGL,
25
n moles of the compound were incubated with 30 g enzyme preparation in THE
buffer (final
volume 250 L). The reaction mixture is treated in the same manner as
described above.
Concentrations of 2-arachidonoylglycerol (2-AG) and arachidonic acid (AA) are
calculated
using external standards. The rate of AA formation is calculated using the
following
equation:
Rate = (T20-TO)/20 min/30 g
[0108] The inhibition of 2-AG metabolism is measured by mixing 25 nmoles of
the
compound with 25 nmoles 2-AG, and 30 pg enzyme preparation in THE buffer
(final volume
of 250 L) as disclosed in Lang et al., Anal. Biochem. (1996) 238:40-45, Qin
et al., Anal.
Biochem. (1998) 261:8-15 and Lang et al., J. Med. Chem. (1999) 42:896-902, for
the FAAH
enzyme assay. Again the reaction mixture is treated in the same manner as
described above
and the concentrations of 2-AG and AA are calculated using external standards.
Percent
inhibition is calculated using the following equation:
% Inhib. = (AA20 - AAO)c/(AA2O - AAO)s
[0109] where (AA20-AAO)c is the amount of arachidonic acid formed over 20 min
from
2-AG with the inhibitor present and (AA20-AAO)s is the amount of arachidonic
acid formed
over 20 min from 2-AG when the inhibitor is not present. In the IC50 studies
of the disclosed
analogs various concentrations of compound are incubated with 25 mnoles 2-AG,
and 30 jig
enzyme preparation in THE buffer (final volume of 250 uL). The reaction
mixtures are
treated as described above and the amount of AA formed was calculated. Prize
software
(GraphPad Software, Inc.) is utilized to calculate IC50 and Ki values.
3. HPLC Conditions for Enzyme Assay
[0110] Chromatographic separation was achieved using an Ultrasphere ODS Pre-
column
(4.6 x 45 min) from Beckman. Hardware consisted of a Waters Millennium HPLC
system
with a 20 pL injection loop. The mobile phase consisted of 8.5% o-phosphoric
acid:acetonitri le (3:7), run isocratically at a rate of 1 mUmin and detection
at 204 mm. The
total run time was 8 min with 2-AG eluting at 3.0 min, and AA at 6.0 min.
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4. Synthesized Compounds
[0111] Some representative MGL inhibitors of Formula (I) that have been
synthesized are
depicted in Tables 1 and 2.
Synthesis of Sulfonyl Fluorides
[01121 Phenylalkylsulfonyl fluorides 4.1, 4.2, and 4.3 (Table 2) were
synthesized by the
method depicted in Scheme 1 starting from commercially available phenylalkyl
alcohols 1. 1,
1.2, and 1.3.
Scheme 1
O O O O
OH a - I b - S- C S
CI - ~:.F
1 2 3 4
1.1: n3 2.1:n=3 3.1: n=3 4.1: n=3
1.2:n=7 2.2:n7 3.2:n7 4.2:n=7
1.3:n=8 2.3:n=8 3.3:n=8 4.3:n=8
[01131 Reagents and conditions for the steps in Scheme I were as follows: Step
a: PPh3,
imidazole, b, MeCN/Et2O, 0 C to RT, 72-85%; Step b (i) t-BuLi, Et?O/pentane, -
78 C, (ii)
SO2Ch, -78 C, 19-23%; Step c: NH4F, acetone, reflux, 91-93%.
A. Phenylalkyl iodides (2)
[0114] A round bottom flask was charged with phenylalkyl alcohol (1) (1
equiv.),
acetonitrile/diethyl ether mixture (1:2), triphenyl phosphine (1.3 equiv.),
imidazole (1.3
equiv.), and iodine (1.3 equiv.). The solution was blanketed with argon and
capped, and the
reaction stirred for 4-5 hours at RT. The resulting mixture was diluted with
diethyl ether,
washed with water, aqueous sodium thiosulfate, and brine, dried (MgSO4), and
evaporated.
Purification by flash column chromatography on silica gel (10% diethyl ether-
hexane) gave
phenylalkyl iodide 2 in 72-85% yield.
B. Phenylalkylsulfonyl chlorides (3)
[01151 A solution of phenylalkyl iodide (2) (1 equiv.) in a mixture of dry n-
pentane/diethyl ether (3:2) was cooled to -78 C under argon, and t-BuLi (2.2
equiv., using a
1.7 M solution of t-BuLi in hexane) was added dropwise over a 2-min period.
The mixture
was stirred for 10 min at -78 C and then was transferred by cannula to a
cooled (-78 C) and
dry solution of SO2C12 in n-pentane over a 20-min period. Following the
addition, the
reaction mixture was stirred for I hour at -78 C and then allowed to warm to
RT over a 3
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hour period. The reaction mixture was quenched with dropwise addition of
water, then
diluted with diethyl ether and the organic phase was separated. The aqueous
phase was
extracted with diethyl ether, the combined organic layer was dried (MgSO4),
and the solvent
was evaporated. Purification by flash column chromatography on silica gel gave
phenylalkylsulfonyl chloride 3 in 19-23% yield.
C. Phenylalkylsulfonyl fluorides (4)
[0116] To a stirred solution of phenylalkylsulfonyl chloride (3) (1 equiv.) in
dry acetone,
was added anhydrous NH4F (2 equiv.) and the mixture refluxed for 2 hours. The
reaction
mixture was cooled to RT, the solvent was evaporated, and the residue obtained
was
dissolved in diethyl ether. The ethereal solution was successively washed with
water and
brine, dried (MgSO4), and concentrated under reduced pressure. Purification by
flash column
chromatography on silica gel gave phenylalkylsulfonyl fluoride 4 in 91-93%
yield.
D. Selected data of synthesized phenylalkylsulfonyl fluorides (4):
3-Phenyl-propanesulfonyl fluoride (4.1)
[0117] 4.1 was confirmed as follows: 1H NMR (200 MHz, CDC13) 8 7.46-7.15 (m,
5H),
3.40-3.27 (in, 2H), 2.82 (t, J= 7.3 Hz, 2H), 2.40-2.21 (m, 2H); mass spectrum
m/z (relative
intensity) 202 (M', 27), 91 (100).
7-Phenyl-heptanesulfonyl fluoride (4.2)
[0118] 4.2 was confirmed as follows: Mass spectrum m/z (relative intensity)
258 (M+,
10), 105 (9), 91 (100).
8-Phenyl-octanesulfonyl fluoride (4.6)
[01191 4.6 was confirmed as follows: 1H NMR (200 MHz, CDC13) 6 7.45-7.05 (m,
5H),
3.40-3.25 (m, 2H), 2.60 (t, J= 7.1 Hz, 2H), 2.10-1.20 (in, 12H).
Synthesis of Sulfonyl Chlorides 12.1-12.4 and Sulfonyl fluorides (13.1-13.4)
and (14.1-
14.4)
[01201 Sulfonyl fluorides (13.1), (13.2), (13.3), (13.4) (14.1), (14.2),
(14.3), (14.4) were
synthesized by a method depicted in Scheme 2 starting from commercially
available 2- or 3-
or 4-anisaldehyde and the appropriate phenoxyalkyl bromide.
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Scheme 2
+ Br
Br.,, f*,.OPh a Ph3P OPh b R1 N OPh e
n n
R2 R3
6 7
5.1:n=4 6.1:n4 7.1:R1=OMe,R2=H,R3=H,n=4
5.2:n=2 6.2:n=2 7.2:R1=H,R2=OMe,R3=H,n=4
7.3:R1=H,R2=H,R3=OMe,n=4
7.4:R1=OMe,R2=H,R3=H,n=2 f
R1 OPh Ri - Br e Rl Br
- n n - n
R2 R3 R2 R3 R2 R3
8 9 10
8.1:R1=OMe,R2=H,R3=H,n=4 9.1:R1=OH,R2=H,R3=H,n=4 10.1: R1=OBn,R2=H,R3=H,n=4
8.2:R1=H,R2=OMe,R3=H,n=4 9.2:R1=H,R2=OH,R3=H,n=4 10.2: R1= H, R2 = OBn, R3 =
H, n = 4
8.3:R1=H,R2=H,R3=OMe,n=4 9.3:R1=H,R2=H,R3=OH,n=4 10.3: R1= H, R2 = H,
R3=OBn,n=4
8.4:R1=OMe,R2=H,R3=H,n=2 9.4:R1=OH,R2=H,R3=H,n=2 10.4: R1=OBn,R2=H,R3=H,n=2
R1 S03Na 9 R1 0'' 0 I h -R, nSO i
n
R2 R3 R2 R3 R2 R3
11 12 13
11.1: R1 = OBn, R2 = H, R3 = H, n = 4 12.1: R1 = OBn, R2 = H, R3 = H, n = 4
13.1: R1 = OBn, R2 = H, R3 = H, n = 4
11.2: R1 = H, R2 = OBn, R3 = H, n = 4 12.2: R1 = H, R2 = OBn, R3 = H, n = 4
13.2: R1 = H, R2 = OBn, R3 = H, n = 4
11.3:R1=H,R2=H,R3=OBn,n=4 12.3:R1=H,R2=H,R3=OBn,n=4 13.3:R1=H,R2=H,R3=OBn,n=4
11.4: R1 = OBn, R2 = H, R3 = H, n = 2 12.4: R1 = OBn, R2 = H, R3 = H, n = 2
13.4: R1 = OBn, R2 = H, R3 = H, n = 2
R1 S0
0
F
R2 R3
14
14.1: R1 = OH, R2 = H, R3 = H, n = 4
14.2: R1 =H, R2=OH, R3=H, n=4
14.3: R1 =H, R2=H, R3=OH, n=4
14.4: R1 = OH, R2 = H, R3 = H, n = 2
[0121] Reagents and conditions for the steps in Scheme 2 were as follows: Step
a: Ph3P,
PhH, reflux, 85-87%; Step b: (Me3Si)2N-K , THF, 0 C, then 2- or 3- or 4-
anisaldehyde 91-
93%; Step c: H2, Pd/C, AcOEt, 30 psi, RT, 6 hours, 95-96%; Step d: BBr3,
CH2C12, -30 C to
RT, 2 hours. 90-93%; Step e: K2C03 acetone, BnBr, reflux, 6 hours, 76-78%-
Step f:
Na2SO3, EtOH/H2O, reflux, 6 hours or microwave; Step g: SOC12, PhH/DMF, N2, 50
C, 3
hours, 37-40% from 10; Step h: NH4F, acetone, N2, reflux, 2 hours, 91-93%;
Step is
BF3'OEt2, HS(CH2)2SH, N2, RT, 1 hour, 68-70%.
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6-Phenoxyhexyltriphenylphosphonium bromide (6.1)
101221 A mixture of 6-phenoxyhexyl bromide (5.1) (2.8 g, 10.9 mmol) and
triphenylphosphine (314 g, 12 mmol) in anhydrous benzene (100 mL), under an
argon
atmosphere, was refluxed for two days. The reaction mixture was allowed to
cool to RT, and
the precipitating product (6.1) was isolated by filtration under reduced
pressure and washed
with anhydrous diethyl ether (4.75 g, white solid, melting point 143-145 C,
84% yield).
[0123] 6.1 was confirmed as follows: 'H NMR (500 MHz, CDCl3) b 7.89-7.85 (in
as dd,
6H), 7.81-7.75 (in as td, 3H), 7.71-7.67 (in as td, 6H), 7.25 (t, J = 7.7 Hz,
2H), 6.91 (t, J = 7.7
Hz, I H), 6.84 (d, J = 7.7 Hz, 2H) 3.95-3.85 (m and t overlapping, especially
3.90, t, J = 6.3
Hz, 4H), 1.79-1.65 (1n, 6H), 1.49 (quintet, J = 7.7 Hz, 2H).
4-Phenoxybutyltriphenylphosphoniium bromide (6.2)
[0124] The title compound was synthesized as in 6.1 using 4-phenoxybutyl
bromide (5.2)
(22.0g, 95.9 mmol) and triphenylphosphine (27.6 g, 105.5 mmol) in anhydrous
benzene (50
mL), to give 6.1 (40.0 g,white solid, melting point 185-186 C, 85% yield).
[0125] 6.2 was confirmed as follows: 'H NMR (500 MHz, CDC13) b 7.88-7.84 (m as
dd,
6H), 7.78-7.76 (in as td, 3H), 7.68-7.65 (m, 6H), 7.25 (t, J = 7.7 Hz, 2H),
6.92 (t, J = 7.7 Hz,
I H), 6.82 (d, J = 7.7 Hz, 2H), 4.09 (t, J = 4.5 Hz, 2H), 4.04-3.98 (m, 2H),
2.25 (quintet, J =
6.4 Hz, 2H), 1.92-1.86 (m, 2H).
1-(4-Methoxyphenyl)-7-phenoxy-l-heptene (7.1)
[0126] To a suspension of 6-phenoxyhexyltriphenylphosphonium bromide (6.1)
(4.60 g,
8.86 mmol) in dry THE (80 mL) at 0 C, under an argon atmosphere was added
potassium
bis(trimethylsilyl)amide (1.76 g, 8.86 mmol). The resulting slurry was stirred
for 5 min at the
same temperature, and then a solution of 4-methoxybenzaldehyde (0.61 g, 4.46
mmol) in dry
THE (10 mL) was added. The reaction mixture was stirred for an additional 10
min and
quenched with saturated aqueous NH4C1 (20 mL). The resulting mixture was
warmed to RT,
diluted with Et?O (100 mL), and the organic phase was separated and the
aqueous phase
extracted with E60. The combined organic layer was washed with brine, dried
over MgSO4,
and the solvent evaporated under reduced pressure. The residue obtained was
purified
through a short column of silica gel, eluting with 5% Et-,O-hexane, to give
the product (7.1)
(1.21 g, 92% yield, predominantly cis, cis:trans = 96:4) as a colorless
liquid.
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[0127] 7.1 was confirmed as follows: 'H NMR (500 MHz, CDC13) b 7.27 (t, J =
7.5 Hz,
2H), 7.21 (d, J = 8.7 Hz, 2H), 6.92 (t, J = 7.5 Hz, 1H), 6.91-6.86 (m,
overlapping signals,
4H), 6.35 (d, J = 11.5 Hz, I H,), 5.57 (dt, J = 11.5 Hz, J = 7.5 Hz, I H),
3.94 (t, J = 6.0 Hz,
2H), 3.81 (s, 3H), 2.41-2.20 (in, 2H), 1.78 (quintet, J = 6.7 Hz, 2H), 1.58-
1.48 (m, 4H).
1-(3-Methoxyphenyl)-7-phenoxy-l-heptene (7.2)
[0128] 1-(3-Methoxyphenyl)-7-phenoxy-l-heptene (7.2) was synthesized as
described
above in 7.1 using 6.1 (3.20 g 6.16 mmol), dry THE (30 mL), potassium
bis(trimethylsilyl)amide (1.23g, 6.16 mmol), and 3-methoxybenzaldehyde (0.28
g, 2.05
mmol). The title compound (7.2) was isolated as a colorless liquid after
purification by flash
column chromatography (0.564 g, 93% yield, predominantly cis, cis:trans =
95:5).
[0129] 7.2 was confirmed as follows: IH NMR (500 MHz, CDC13) b 7.27-7.21 (m,
3H),
6.92 (t, J = 7.0 Hz, I H), 6.90-6.86 (m, 3H), 6.81 (t, J = 1.5 Hz, I H), 6.78
(dd, J = 8.5 Hz, J =
1.5Hz,1H),6.39(d,J=11.7Hz,'1H),5.67(dt,J=11.7Hz, J = 7.5 Hz,1H),3.94(t,J=6.5
Hz, 2H), 3.80 (s, 3H), 2.37 (q, J = 6.5, 2H), 1.78 (quintet, J = 6.5 Hz, 2H),
1.56- 1.48 (in,
4H).
1-(2-Methoxyphenyl)-7-phenoxy-l-heptene (7.3)
[0130] 1-(2-Methoxyphenyl)-7-phenoxy-l-heptene (7.3) was synthesized as
described
above for 7.1 using 6.1 (2.0 g, 3.85 mmol), dry THE (30 mL), potassium
bis(trimethylsilyl)amide (0.77g, 3.85 mmol), and 2-methoxybenzaldehyde (0.20
g, 1.47
mmol). The title compound (7.3) was isolated as a colorless liquid after
purification by flash
column chromatography (0.396 g, 91% yield, predominantly cis, cis:trans =
93:7).
[0131] 7.3 was confirmed as follows: 1H NMR (500 MHz, CDC13) 8 7.29-7.21 (m,
4H),
6.94-6.87 (in, 5H), 6.52 (d, J = 11.2 Hz, I H), 5.73 (dt, J = 11.2 Hz, J = 7.5
Hz, I H), 3.93 (t, J
= 6.7 Hz, 2H), 3.83 (s, 3H), 2.28 (m as q, J = 7.2 Hz, 2H), 1.76 (quintet, J =
7.2 Hz, 2H),
1.53-1.46 (m, 4H).
1-(4-Methoxyphenyl)-7-phenoxy-l-pentene (7.4)
[0132] 1-(4-Methoxyphenyl)-7-phenoxy-l-pentene (7.4) was synthesized as
described in
7.1 using 6.2 (29.0 g, 58.8 mmol), dry THE (200 mL), potassium
bis(trimethylsilyl)amide
(11.7 g, 58.8 mmol) and 4-methoxybenzaldehyde (2.9 g, 14.7 mmol). The title
compound
(7.4) was isolated as a colorless liquid after purification by flash column
chromatography
(3.69 g, 93% yield, predominantly cis, cis:trans = 96:4).
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[0133] 7.4 was confirmed as follows: 'H NMR (500 MHz, CDC13) b 7.26 (t, J =
7.5 Hz,
2H), 7.22 (d, J = 8.7 Hz, 2H), 6.92 (t, J = 7.5 Hz, IH), 6.87 (d, J = 7.5 Hz,
2H), 6.85 (d, J =
8.7Hz,2H),6.39(d,J=11.5Hz,1H),5.60(dt,J=11.5Hz, J = 7.0 Hz,1H),3.98(t,J=6.0
Hz, 2H), 3.80 (s, 3H), 2.51 (m as qd, J = 7.5 Hz, J = 2.1 Hz, 2H), 1.94
(quintet, J = 6.7 Hz
2H).
1-(4-Methoxyphenyl)-7-phenoxy-heptane (8.1)
[0134] To a stirred solution of 7.1 (1.19 g, 4.03 mmol) in AcOEt (40 mL) at RT
was
added 10% Pd/C (0.18 g, 15% w/w), and the resulting suspension was
hydrogenated (30 psi,
6 hrs). The catalyst was removed by filtration through celite, and the
filtrate was evaporated
under reduced pressure to give the title compound (8.1) as a white solid (1.14
g, 95% yield,
melting point 32-34 C).
[0135] 8.1 was confirmed as follows: 'H NMR (500 MHz, CDC13) b 7.30 (t, J =
8.5 Hz,
2H), 7.11 (d, J = 8.2 Hz, 2H), 6.95 (t, J = 8.5 Hz, 1H), 6.92 (d, J = 8.5 Hz
2H), 6.84 (d, J =
8.2 Hz, 2H), 3.97 (t, J = 6.7 Hz, 2H), 3.81,(s, 3H) 2.57 (t, J = 7.5 Hz, 2H),
1.78 (quintet, J =
6.7 Hz, 2H), 1.62 (quintet, J = 7.5 Hz, 2H), 1.48 (quintet, J = 7.5 Hz, 2H),
1.44-1.34 (m, 4H).
1-(3-Methoxyphenyl)-7-phenoxy-heptane (8.2)
[0136] 1-(3-Methoxyphenyl)-7-phenoxy-heptane (8.2) was synthesized as
described in
8.1 using 7.2 (0.55 g, 1.86 mmol), AcOEt (20 mL), and 10% Pd/C (0.080 -,15%
w/w). The
title compound (8.2) was isolated as a colorless viscous liquid (0.53 g, 96%
yield).
[0137] 8.2 was confirmed as follows: 'H NMR (500 MHz, CDC13) b 7.27 (t, J =
7.0 Hz,
2H), 7.19 (t, J = 7.4 Hz, I H), 6.92 (t, J = 7.0 Hz,
1H).6.89(d,J=7.0Hz,2H),6.77(d,J=
7.4 Hz, 1H), 6.73-6.71 (m, 2H), 3.94 (t, J = 6.5Hz, 2H), 3.79 (s, 3H), 2.58
(t, J = 7.5Hz, 2H),
1.77 (quintet, J = 6.7 Hz, 2H), 1.62 (quintet, J = 7.2 Hz, 2H), 1.50- 1.42
(in, 2H), 1.42-1.34
(m, 4H).
1-(2-Methoxyphenyl)-7-phenoxy-heptane (8.3)
[0138] 1-(2-Methoxyphenyl)-7-phenoxy-heptane (8.3) was synthesized as
described in
8.1 using 7.3 (0.35 g, 1.18 mmol), AcOEt (20 mL), and 10% Pd/C (0.050 g, 14%
w/w). The
title compound (8.3) was isolated as a colorless viscous liquid (0.33 g, 95%
yield).
[0139] 8.3 was confirmed as follows: 'H NMR (500 MHz, CDC13) 6 7.27 (t, J =
7.5 Hz,
2H), 7.16 (t, J = 7.5 Hz, 1 H), 7.12 (d, J = 7.5 Hz, 1 H), 6.94-6.83 (m, 5H),
3.95 (t, J = 6.5 Hz,
2H), 3.81 (s, 3H), 2.60 (t, J = 7.7, 2H), 1.78 (quintet, J = 7.0 Hz, 2H), 1.59
(quintet, J = 7.0
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Hz, 2H), 1.48-1.43 (in, 2H), 1.42-1.38 (m, 4H).
1-(4-Methoxyphenyl)-5-phenoxy-pentane (8.4)
[0140] 1-(4-Methoxyphenyl)-5-phenoxy-pentane (8.4) was synthesized as
described in
8.1 using 7.4 (3.67 g, 13.69 mmol), AcOEt (100 mL), and 10% Pd/C (0.550 g, 15%
w/w).
The title compound (8.3) was isolated as a white solid (m p 32-34 C) in 95%
yield (3.52 g).
[0141] 8.4 was confirmed as follows: 'H NMR (500 MHz, CDC13) 6 7.27 (t, J =
7.5 Hz,
2H), 7.09 (d, J = 8.5 Hz, 2H), 6.92 (t, J = 7.5Hz, 1H), 6.88 (d, J = 7.5 Hz,
2H), 6.82 (d, J =
8.5 Hz, 2H), 3.94 (t, J = 6.5 Hz, 2H), 3.78 (s, 3H), 2.58 (t, J = 7.7 Hz, 2H),
1.80 (quintet, J =
6.7 Hz, 2H), 1.66 (quintet, J = 7.0 Hz, 2H), 1.49 (quintet, J = 7.5 Hz, 2H).
7-Bromo-l-(4-hydroxy-phenyl)-heptane (9.1)
[0142] To a stirred solution of 8.1 (1.1 g, 3.69 mmol) in anhydrous CH2C12,
(40 mL), at -
30 C, under an argon atmosphere was added BBr3 (8 mL, 8 mmol, using a 1 M
solution in
CH2C12) and the mixture gradually warmed to RT (2 hours). Unreacted boron
tribromide was
destroyed by addition of aqueous saturated NaHCO3 solution (10 mL) to the
reaction mixture
at 0 C. The resulting mixture was warmed to RT and diluted with Et20 (40 mL).
The
organic layer was separated and the aqueous phase extracted with Et-'O. The
combined
organic layer was washed with brine, dried over MgSO4, and the solvent
evaporated under
reduced pressure. The residue obtained was chromatographed through a short
column of
silica gel, eluting with 20% E60-hexane to give 8.1 (0.930 g, 93% yield) as a
viscous liquid.
[0143] 9.1 was confirmed as follows: 'H NMR (500 MHz, CDC13) 6 7.03 (d, J =
8.5 Hz,
2H), 6.74 (d, J = 8.5 Hz, 2H), 4.59 (br s, 1H), 3.34 (t, J = 6.7 Hz, 2H), 2.53
(t, J =7.7 Hz, 2H),
1.84 (quintet, J = 7.0 Hz, 2H), 1.57 (quintet, J = 7.5 Hz, 2H), 1.46-1.38 (m,
2H), 1.36-1.31
(in, 4H).
7-Bromo-l-(3-hydroxy-phenyl)-heptane (9.2)
[0144] 7-Bromo- I-(' -hydroxy-phenyl)-heptane (9.2) was synthesized as in 9.1
using 8.2
(0.50 g, 1.68 mmol), in anhydrous CH2C12 (16 mL), and BBr3 (1 M solution in
CH2C12, 3.7
mL, 3.7 mmol). The title compound (9.2) was isolated as a viscous liquid after
purification
by flash column chromatography (0.420 g, 92% yield).
[0145] 9.2 was confirmed as follows: 'H NMR (500 MHz, CDC13) 6 7.14 (t, J =
8.0 Hz,
1 H), 6.75 (d, J = 8.0 Hz, 1 H), 6.66-6.63 (d and dd overlapping, 2H), 4.67
(br s, 1 H), 3.40 (t, J
= 6.7 Hz, 2H), 2.56 (t, J = 7.7 Hz, 2H), 1.85 (quintet, J = 7.0 Hz, 2H), 1.62
(quintet, J = 7.5
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Hz, 2H), 1.46-1.38 (m, 2H), 1.36-1.32 (m, 4H).
7-Bromo-l-(2-hydroxy-phenyl)-heptane (9.3)
[0146] 7-Bromo-l-(2-hydroxy-phenyl)-heptane (9.3) was synthesized as in 9.1
using 8.3
(0.30 g, 1.01 mmol) in anhydrous CH2Ch (10 mL), and BBr3 (1 M solution in
CH2Ch, 2.2
mL, 2.2 mmol). The title compound (9.3) was isolated as a viscous liquid after
purification
by flash column chromatography (0.247 g, 90% yield).
[0147] 9.3 was confirmed as follows: 'H NMR (500 MHz, CDC13) b 7.11 (dd, J =
7.5 Hz,
J = 1.5 Hz, 1H), 7.07 (td, J = 7.5 Hz, J = 1.5 Hz, 1H), 6.87 (td, J = 7.5 Hz,
J = 1.5 Hz, 1H),
6.75 (dd, J = 7.5 Hz, J = 1.5 Hz, 1H), 4.62 (br s, I H), 3.40 (t, J = 7.0 Hz,
2H), 2.60 (t, J = 8.0
Hz, 2H), 1.85 (quintet, J = 6.7 Hz, 2H), 1.62 (quintet, J = 7.2 Hz, 2H), 1.4
(quintet, J = 7.5
Hz, 2H), 1.40-1.35 (m, 4H).
5-Bromo-l-(4-hydroxy-phenyl)-pentane (9.4)
[0148] 5-Bromo-l-(4-hydroxy-phenyl)-pentane (9.4) was synthesized as in 9.1
using 8.4
(3.43 g, 12.7 mmol) in anhydrous CH2CI2 (120 mL), and BBr3 (1 M solution in
CH2CI7, 32
mL, 32 mmol). The title compound (9.4) was isolated as a viscous liquid after
purification by
flash column chromatography (2.84 g, 92% yield).
[0149] 9.4 was confirmed as follows: 'H NMR (500 MHz, CDC13) b 7.04 (d, J =
8.7 Hz,
2H),6.75(d,J=8.7Hz,2H),4.68(brs,1H),3.34(t,J= 6.7 Hz, 2H), 2.55 (t, J = 7.7
Hz,
2H), 1.88 (quintet, J = 7.7 Hz, 2H), 1.60 (quintet, J = 7.7 Hz, 2H), 1.46
(quintet, J = 7.5 Hz,
2H).
7-Bromo-l-(4-benzyloxy-phenyl)-heptane (10.1)
[0150] To a stirred solution of 9.1 (0.9 g, 3.32 mmol) in anhydrous acetone
(40 mL), was
added anhydrous K,)C03 (1.38 g, 10 mmol) and benzyl bromide (0.624 g, 3.65
mmol) and the
mixture was refluxed for 6 hours. The reaction mixture was cooled to RT,
diluted with
acetone, and solid materials were filtered off. The filtrate was evaporated
under reduced
pressure, and the residue obtained was dissolved in diethyl ether (50 mL). The
ethereal
solution was washed with water and brine, dried (MgSO4), and evaporated.
Purification by
flash column chromatography on silica gel (5% Et2O-hexane) afforded 10.1
(0.938 g, 78%
yield) as a white solid (melting point 32-34 C).
[0151] 10.1 was confirmed as follows: ' H NMR (500 MHz, CDC13) d 7.43 (d, J =
7.0 Hz,
2H), 7.38 (t, J = 7.0 Hz, 2H), 7.32 (t, J = 7.0 Hz 1H), 7.08 (d, J = 8.7 Hz,
2H) 6.90(d, J= 8.7
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Hz 2H), 5.04 (s, 2H), 3.34 (t, J = 7.0 Hz, 2H), 2.54 (t, J = 7.7 Hz, 2H), 1.85
(quintet, H = 7.5
Hz, 2H), 1.58 (quintet, J = 7.5 Hz, 2H), 1.46- 1.38 (m, 2H), 1.37 - 1.30 (in,
4H).
7-Bromo-l-(3-benzyloxy-phenyl)-heptane (10.2)
[0152] 7-Bromo-1-(3-benzyloxy-phenyl)-heptane (10.2) was prepared as in 10.1
using
9,2 (0.4 g, 1.48 mmol), K2C03 (0.612 g, 4.44 mmol) and benzyl bromide (0.278
g, 1.63
mmol). The title compound (10.2) was isolated as a viscous liquid after
purification by flash
column chromatography (0.411 g, 77% yield).
[0153] 10.2 was confirmed as follows: 'H NMR (500 MHz, CDC13) 8 7.44 (d, J =
7.5 Hz,
2H), 7.39 (t, J = 7.5 Hz, 2H), 7.32 (t, J = 7.5 Hz I H), 7.19 (t, J = 7.2 Hz,
I H) 6.83-6.77 (in,
3H), 5.05 (s, 2H), 3.40 (t, J = 6.77 Hz, 2H), 2.56 (t, J = 7.7 Hz, 2H), 1.84
(quintet, J = 7.0 Hz,
2H), 1.60 (quintet, J = 7.7 Hz, 2H), 1.42 (quintet, J = 7.0 Hz, 2H), 1.35-1.32
(m, 4H).
7-Bromo-l-(2-benzyloxy-phenyl)-heptane (10.3)
[0154] 7-Bromo-l-(2-benzyloxy-phenyl)-heptane (10.3) was prepared as in 10.1
using
9.3 (0.23 g, 0.85 mmol), K2CO3 (0.352 g, 2.55 mmol) and benzyl bromide (0.16
g, 0.935
mmol). The title compound (10.3) was isolated as a viscous liquid after
purification by flash
column chromatography (0.24 g, 78% yield).
[0155] 10.3 was confirmed as follows: 'H NMR (500 MHz, CDC13) 8 7.44 (d, J =
7.5 Hz,
2H), 7.39 (t, J = 7.5 Hz, 2H), 7.32 (t, J = 7.5 Hz 1H), 7.18-7.13 (in, 2H),
6.92-6.88 (m, 2H),
5.08 (s, 2H), 3.37 (t, J = 7.0 Hz, 2H), 2.67 (t, J = 7.7 Hz, 2H), 1.82
(quintet, J = 7.2 Hz, 2H),
1.62 (quintet, J = 7.5 Hz, 2H), 1.39 (quintet, J = 7.7 Hz, 2H), 1.36-1.32 (in,
4H).
5-Bromo-l-(4-benzyloxy-phenyl)-pentane (10.4)
[0156] 5-Brozno-l-(4-benzyloxy-phenyl)-pentane (10.4) was prepared as in 10.1
using
9.4 (2.99 g, 12.3 mmol), K2C03 (4,24 g, 30.75 mmol) and benzyl bromide (2.31
g, 13.53
mmol). The title compound (10.4) was isolated as a white semi-solid after
purification by
flash column chromatography (3.11 g, 76% yield).
[0157] 10.4 was confirmed as follows: 'H NMR (500 MHz, CDC13) 6 7.42 (d, J =
7.5 Hz,
2H), 7.37 (t, J = 7.5 Hz, 2H), 7.31 (t, J = 7.5 Hz 1 H), 7.08 (d, J = 8.5 Hz,
2H), 6.90 (d, J = 8.5
Hz, 2H), 5.03 (s, 2H), 3.39 (t, J = 6.7 Hz, 2H), 2.56 (t, J = 7.7 Hz, 2H),
1.87 (quintet, J = 6.7
Hz, 2H), 1.61 (quintet J = 7.7 Hz, 2H), 1.46 (quintet J = 6.7 Hz, 2H).
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7-(4-Benzyloxy-phenyl)-heptanesulfonic acid sodium salt (11.1)
[0158] A stirred mixture of 10.1 (0.9 g, 2.50 mmol) and anhydrous Na2SO3
(0.423 g, 3.36
mmol) in EtOH (20 mL)/H7O (10 ml) was heated under reflux (6 hours) or
microwaved using
a CEM-discover system (ram time: 2 min, hold time: 5 min, temperature: 150 C,
pressure:
250 psi, power: 250 W). The reaction mixture was cooled to RT, and the solvent
evaporated
under reduced pressure. The residue obtained was scrupulously dried under high
vacuum,
and the crude product (11.1, pale yellow solid) was used in the next step
without further
purification.
7-(3-Benzyloxy-phenyl)-heptanesulfonic acid sodium salt (11.2)
[0159] Following the procedure described for 11. 1 using the 10.2 (0.4 g, 1.1
mmol),
Na2SO3 (0.19 g, 1.5 mmol) and EtOH (8 mL)/H,O (4 ml) mixture, the crude 11.2
was
obtained and used in the next step without further purification.
7-(2-Benzyloxy-phenyl)-heptanesulfonic acid Sodium salt (11.3)
[0160] Following the procedure described for 11.1 using 10.3 (0.23 1 g, 0.64
mmol),
Na2SO3 (0.11 g, 0.89 mmol) and EtOH (8 mL)/H2O (4 ml) mixture, the crude 11.3
was
obtained and used in the next step without further purification.
5-(4-Benzyloxy-phenyl)-pentanesulfonic acid Sodium salt (11.4)
[0161] Following the procedure described for 11.1 using 10.4 (0.95 g, 2.85
mmol),
Na2SO3 (0.50 g, 4.0 mmol) and EtOH (25 mL)/H2O (7 ml) mixture, the crude 11.4
was
obtained and used in the next step without further purification.
7-(4-Benzyloxy-phenyl)-heptanesulfonyl chloride (12.1)
[01621 To a stirred suspension of 11.1 (0.96 g, 2.50 mmol) in anhydrous
benzene (20
mL)/DMF (2 ml), was added thionyl chloride (0.89 g, 7.5 mmol) and the
resulting mixture
was heated at 50 C for 3 hours under argon. The reaction mixture was quenched
by dropwise
addition of water (10 mL) at RT and extracted with diethyl ether. The organic
layer was
washed with brine, dried (MgSO4), and the solvent evaporated under reduced
pressure.
Purification by flash column chromatography on silica gel (20% diethyl ether-
hexane)
afforded 12.1 in 40% yield from 10.1 (0.38 g, white solid, melting point 33-35
C).
[0163] 12.1 was confirmed as follows: IH NMR (500 MHz, CDC13) 6 7.44 (d, J =
7.5 Hz,
2H), 7.38 (t, J = 7.5 Hz, 2H), 7.32 (t, J = 7.5 Hz I H), 7.08 (d, J = 8.5 Hz,
2H), 6.90(d, J = 8.5
Hz, 2H), 5.04 (s, 2H), 3.64 (m as t, half of an AA'XX' system, 2H), 2.55 (t, J
= 7.5 Hz, 2H),
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2.03 (quintet, J = 7.7 Hz, 2H), 1.62-1.54 (in, 2H), 1.52-1.46 (in, 2H), 1.40-
1.30 (m, 4H).
7-(3-Benzyloxy-phenyl)-heptanesulfonyl chloride (12.2)
[0164] 7-(3-Benzyloxy-phenyl)-heptanesulfonyl chloride (12.2) was synthesized
as
described in 12.1 using 11.2 (0.42 g, 1.1 mmol) and thionyl chloride (0.36 g,
3 mmol) in
benzene (9 mL)/DMF (1 mL). Purification by flash column chromatography on
silica gel
gave the title compound (0.163 g, 39% yield from 10.2) as a viscous liquid.
[0165] 12.2 was confirmed as follows: 'H NMR (500 MHz, CDC13) 6 7.44 (d, J
=7.5 Hz,
2H), 7.39 (t, J =7.5 Hz, 2H), 7.32 (t, J = 7.5 Hz, 1H), 7.19 (t, J = 7.2 Hz,
IH), 6.82-6.77 (m,
3H), 5.05 (s, 2H), 3.64 (m as t, half of an AA'XX' system, 2H), 2.58 (t, J =
7.5 Hz, 2H), 2.02
(quintet, J = 7.5 Hz, 2H), 1.62 (quintet, J = 7.5 Hz, 2H), 1.48 (quintet, J =
7.5 Hz, 2H), 1.42-
1.32 (in, 4H).
7-(2-Benzyloxy-phenyl)-heptanesulfonyl chloride (12.3)
[0166] 7-(2-Benzyloxy-phenyl)-heptanesulfonyl chloride (12.3) was synthesized
as
described in 12.1 using 11.3 (0.46 g, 0.64 mmol) and thionyl chloride (0.228
g, 1.92 mmol) in
benzene (9 mL)/DMF (1 mL). Purification by flash column chromatography on
silica gel
gave the title compound (0.092 g, 38% yield from 10.3) as a viscous liquid.
[0167] 12.3 was confirmed as follows: 'H NMR (500 MHz, CDC13) 6 7.44 (d, J =
7.5 Hz,
2H), 7.39 (t, J = 7.5 Hz, 2H), 7.33 (t, J = 7.5 Hz I H), 7.18-7.33 (m, 2H),
6.92-6.88 (m, 2H),
5.08 (s, 2H), 3.58 (in as t, half of an AA'XX' system, 2H), 2.67 (t, J = 7.7
Hz, 2H), 1.99
(quintet, J = 7.5 Hz, 2H), 1.62(quintet, J = 7.5 Hz, 2H), 1.46-1.4 (in, 2H),
1.36-1.32 (m, 4H).
5-(4-Benzyloxy-phenyl)-pentanesulfonyl chloride (12.4)
[0168] 5-(4-Benzyloxy-phenyl)-pentanesulfonyl chloride (12.4) was synthesized
as
described in 12.1 using 11.4 (0.96 g, 2.85 mmol) and thionyl chloride (1.00 g,
8.55 mmol) in
benzene (27 mL)/DMF (3 mL). Purification by flash column chromatography on
silica gel
gave the title compound (0.36 g, 37% yield from 10.4) as a white solid
(melting point 58-
60 C).
[0169] 12.4 was confirmed as follows: 'H NMR (500 MHz, CDCI3) b 7.43 (d, J =
7.5 Hz,
2H),7.38(t,J=7.5Hz,2H),7.32(t,J=7.5Hz1H),7.07 (d, J = 8.7 Hz, 2H), 6.90 (d, J
= 8.7
Hz, 2H), 5.04 (s, 2H), 3.64 (m as t, half of an AA'XX' system, 2H), 2.56 (t, J
= 7.2 Hz, 2H),
2.06 (quintet, J = 7.7 Hz, 2H), 1.66 (quintet, J = 7.5 Hz, 2H), 1.46 (quintet,
J = 7.7 Hz, 2H).
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7-(4-Benzyloxy-phenyl)-heptanesulfonyl fluoride (13.1)
[0170] To a stirred solution of 12.1 (0.345 g, 0.9 mmol) in dry acetone (20
mL), was
added anhydrous NH4F (0.066 g, 1.8 mmol) and the mixture refluxed for 2 hours.
The
reaction mixture was cooled to RT, the solvent was evaporated, and the residue
obtained was
dissolved in diethyl ether (20 mL). The ethereal solution was successively
washed with
water and brine, dried (MgSO4), and concentrated under reduced pressure.
Purification by
flash column chromatography on silica gel (20% diethyl ether-hexane) afforded
13.1 (0.306
g, 93% yield) as a white solid (melting point 35-38 C).
[0171] 13.1 was confirmed as follows: 'H NMR (500 MHz, CDC13) 6 7.43 (d, J =
7.5 Hz,
2H), 738 (t, J = 7.5 Hz, 2H), 7.32 (t, J = 7.5 Hz 1H), 7.08 (d, J = 8.7 Hz,
2H), 6.90 (d, J= 8.7
Hz, 2H), 5.04 (s, 2H), 3.36-3.32 (7n, 2H), 2.54 (t, J = 7.5 Hz, 2H), 1.94
(quintet, J = 7.5 Hz,
2H), 1.62-1.54 (m, 2H), 1.52-1.44 (m, 2H), 1.40-1.30 (m, 4H).
7-(3-Benzyloxy-phenyl)-heptanesulfonyl fluoride (13.2)
[0172] 7-(3-Benzyloxy-phenyl)-heptanesulfonyl fluoride (13.2) was prepared as
in 13.1
using 12.2 (0.149 g, 0.39 mmol) and NH4F (0.029 g, 0.78 mmol) in dry acetone
(10 mL).
Purification by flash column chromatography on silica gel gave the title
compound (0.128 g,
91% yield) as a viscous liquid.
[0173] 13.2 was confirmed as follows: 'H NMR (500 MHz, CDC13) 6 7.43 (d, J =
7.5 Hz,
2H), 7.39 (t, J =7.5 Hz, 2H), 7.32 (t, J =7.5 Hz, 1 H), 7.19 (t, J = 7.2 Hz, 1
H), 6.82-6.77 (m,
3H), 5.05 (s, 2H), 3.36-3.32 (m, 2H), 2.58 (t, J = 7.5 Hz, 2H), 1.93 (quintet,
J = 7.7 Hz, 2H),
1.61 (quintet, J = 7.5 Hz, 2H), 1.48 (quintet, J = 7.2 Hz, 2H), 1.42-1.32 (m,
4H).
7-(2-Benzyloxy-phenyl)-heptanesulfonyl fluoride (13.3)
[0174] 7-(2-Benzyloxy-phenyl)-heptanesulfonyl fluoride (13.3) was prepared as
in 13.1
using 12.3 (0.09 g, 0.236 mmol) and NH4F (0.018 g, 0.486 mmol) in dry acetone
(10 mL).
Purification by flash column chromatography gave the title compound (0.079 g,
92% yield)
as a viscous liquid.
[0175] 13.3 was confirmed as follows: 'H NMR (500 MHz, CDC13) 6 7.43 (d, J =
7.2 Hz,
2H), 7.39 (t, J = 7.2 Hz, 2H), 7.33 (t, J = 7.2 Hz 1H), 7.17-7.14 (m, 2H),
6.92-6.89 (m, 2H),
5.08 (s, 2H), 3.35-3.32 (in, 2H), 2.67 (t, J = 7.5 Hz, 2H), 1.89 (quintet, J =
7.7 Hz, 2H), 1.62
(quintet, J = 7.5 Hz, 2H), 1.46-1.4 (m, 2H), 1.36-1.32 (m, 4H).
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5-(4-Benzyloxy-phenyl)-pentanesulfonyl fluoride (13.4)
[0176] 5-(4-Benzyloxy-phenyl)-pentanesulfonyl fluoride (13.4) was synthesized
as
described in 13.1 using 12.4 (0.3 g, 0.87 mmol) and NH4F (0.06 g, 1.64 mmol)
in dry acetone
(40 mL). Purification by flash column chromatography on silica gel gave the
title compound
(0.266 g, 91% yield) as a white solid (m p 66-68 C).
[0177] 13.4 was confirmed as follows: 'H NMR (500 MHz, CDC13) 6 7.43 (d, J =
7.5 Hz,
2H),7.38(t,J=7.5Hz,2H),7.32(t,J=7.5Hz1H),7.08 (d, J= 8.0 Hz, 2H), 6.90 (d, J =
8.0
Hz, 2H), 5.04 (s, 2H), 3.35-3.32 (m, 2H), 2.58 (t, J = 7.5 Hz, 2H), 1.96
(quintet, J = 7.7 Hz,
2H), 1.65 (quintet J = 7.5 Hz, 2H), 1.50 (quintet, J = 7.5 Hz, 2H).
7-(4-Hydroxy-phenyl)-heptanesulfonyl fluoride (14.1)
[0178] To a solution of 13.1 (0.182 g, 0.5 mmol) in ethanedithiol (10 mL), at
RT, under
an argon atmosphere was added BF3'Et,O (0.282 g, 2.0 mmol). The reaction
mixture was
stirred at RT for 1 hour and then diluted with diethyl ether (20 mL) and water
(10 mL). The
organic layer was separated and the aqueous phase extracted with diethyl
ether. The
combined organic layer was washed with brine, dried over MgSO4, and
concentrated under
reduced pressure. The residue obtained was chromatographed through a column of
silica gel
eluting with 50% diethyl ether-hexane to give 14.1 (0.096 g, 70% yield) as a
white solid
(melting point 47-51 C).
[0179] 14.1 was confirmed as follows: 'H NMR (500 MHz, CDC13) 6 7.08 (d, J =
9.0 Hz,
2H), 6.90 (d, J = 9.0 Hz, 2H), 4.08 (br s, 2H), 3.36-3.32 (in, 2H), 2.55 (t, J
= 8.0 Hz, 2H),
1.98-1.90 (m, 2H), 1.62-1.54 (m, 2H), 1.52-1.44 (in, 2H) 1.38-1.34 (in, 4H).
7-(3-Hydroxy-phenyl)-heptanesulfonyl fluoride (14.2)
[0180] 7-(3-Hydroxy-phenyl)-heptanesulfonyl fluoride (14.2) was synthesized as
described in 14.1 using 13.2 (0.1 g, 0.26 mmol) in ethanedithiol (5 mL) and
BF3'Et2O (0.14 g,
1.0 mmol). Purification by flash column chromatography on silica gel gave 14.2
(0.049 g,
69% yield) as a viscous liquid.
[0181] 14.2 was confirmed as follows: 'H NMR (500 MHz, CDC13) 6 7.14 (t, J =
7.5 Hz,
1H), 6.74 (d, J = 7.5 Hz, 1H), 6.66-6.64 (in, 2H), 4.70 (br s 1H), 336-3.32
(m, 2H), 2.56 (t, J
= 7.7 Hz, 2H), 1.94 (quintet, J = 7.7 Hz, 2H), 1.61 (quintet, J = 7.5 Hz, 2H),
1.49 (quintet, J =
7.2 Hz, 2H), 1.42-1.32 (in, 4H).
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7-(2-Hyydroxy-phenyl)-heptanesulfonyl fluoride (14.3)
[0182] 7-(2-Hydroxy-phenyl)-heptanesulfonyl fluoride (14.3) was synthesized as
described in 14.1 using 13.3 (0.065 g, 0.17 mmol) in ethanedithiol (5 mL) and
BF3'Et2O
(0.092 g, 0.65 mmol). Purification by flash column chromatography gave 14.3
(0.033 g, 70%
yield) as a viscous liquid.
[0183] 14.3 was confirmed as follows: 'H NMR (500 MHz, CDC13) b 7.11-7.06 (m,
2H),
6.87 (dt, J = 7.7 Hz, J = 1.0 Hz, 1 H),6.75 (dd, J = 7.7 Hz, J = 1.0 Hz, 1 H),
4.70 (br s, 1 H),
3.35-3.32 (m, 2H), 2.61 (t, J = 7.2 Hz, 2H), 1.94 (quintet, J = 7.7 Hz, 2H),
1.66-1.58 (m, 2H),
1.52-1.46 (m, 2H), 1.42-1.34 (in, 4H).
5-(4-Hydroxy-phenyl)-pentanesulfonyl fluoride (14.4)
[01841 5-(4-Hydroxy-phenyl)-pentanesulfonyl fluoride (14.4) was synthesized as
described in 14.1 using 13.4 (0.28 g, 0.83 minol) in ethanedithiol (10 mL) and
BF3'Et2O (0.47
g, 3.32 mmol). Purification by flash column chromatography on silica gel gave
14.4 (0.139
g, 68% yield) as a white solid (m p 32-35 C).
[0185] 14.4 was confirmed as follows: 'H NMR (500 MHz, CDC13) S 7.02 (d, J =
8.2 Hz,
2H), 6.76 (d, J = 8.2 Hz, 2H), 4.65 (br s, 1H), 3.36-3.32 (m, 2H), 2.58 (t, J
= 7.2 Hz, 2H),
1.96 (quintet, J = 7.7 Hz, 2H), 1.64 (quintet, J = 7.5 Hz, 2H), 1.50 (quintet,
J = 7.5 Hz, 2H).
Synthesis of Sulfonvl fluoride 17
[01861 Sulfonyl fluoride (17) (shown in Scheme 3) was synthesized by a method
depicted
in Scheme 3 starting from commercially available 4-phenoxybutyl bromide (5.2).
Scheme 3
(j-OBr a- O SO3Na b 0\ 0 c - j\ O S O
5.2 15 16 17
[0187] Reagents and conditions for the steps in Scheme 3 were as follows: Step
a:
Na2SO3, EtOH/H7O, reflux, 6 hours or microwave; Step b: SOCK, PhH/DMF, N2, 50
C, 3
hours, 40%; Step c: NH4F, acetone, N2, reflux, 2 hours, 91%.
4-Phenoxybutyl sulfonic acid sodium salt (15)
[0188] Following the procedure described for 11.1 using 5.2 (1.0 g, 4.37
mmol), Na2SO3
(0.77 g, 6.11 mmol), and EtOH (30 mL)/ H2O (10 mL) mixture, the crude (15) was
obtained
and used in the next step without further purification.
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4-Phenoxybutyl sulfonyl chloride (16)
[0189] 4-Phenoxybutyl sulfonyl chloride (16) was synthesized as described in
12.1 using
15 (1.0 g, 4.37 mmol) and thionyl chloride (1.55 g, 13.0 mmol) in benzene
(401nL)/DMF (4
mL). Purification by flash column chromatography on silica gel afforded 15
(0.434 g, 40%
yield) as a white solid (melting point 65-67 C).
[0190] 16 was confirmed as follows: 'H NMR (500 MHz, CDC13) 8 7.29 (t, J = 8.2
Hz,
2H), 6.97 (t, J = 8.2 Hz, I H), 6.89 (d, J = 8.2 Hz, 2H), 4.04 (t, J = 5.7 Hz,
2H), 3.80 (m as t,
half of an AA'XX' system, 2H), 2.29 (quintet, J = 7.7 Hz, 2H), 2.01(quintet, J
= 7.7 Hz, 2H).
4-Phenoxybutylsulfonyl fluoride (17)
[0191] 4-Phenoxybutylsulfonyl fluoride (17) was synthesized as in 13.1 using
16 (0.4 g,
1.6 mmol) and NH4F (0.118 g, 3.2 mmol) in dry acetone (20 mL). Purification by
flash
column chromatography on silica gel gave 17 (0.338g, 91% yield) as a white
solid (m p 74-
76 C).
[0192] 17 was confirmed as follows: 'H NMR (500 MHz, CDC13) 6 7.29 (t, J = 7.5
Hz,
2H), 6.97 (t, J = 7.5 Hz, 1 H), 6.89 (d, J = 7.5 Hz, 2H), 4.03 (t, J = 5.5 Hz,
2H), 3.52-3.48 (m,
2H), 2.20 (quintet, J = 7.7 Hz, 2H), 2.00(quintet, J = 8.0 Hz, 2H).
Synthesis of sulfonyl esters (18)
[0193] Sulfonyl ester 18 (shown in Scheme 4) was synthesized by a method
depicted in
Scheme 4 starting from 12.1.
Scheme 4
BnO 06S O ' a BnO 068 OM,
12.1 18
[0194] Reagents and conditions for Scheme 4 were as follows: Step a: MeOH, RT,
overnight, 82%.
7-(4-Benzyloxy-phenyl)-heptane-l-sulfonic acid methyl ester (18)
[0195] A solution of 12.1 (0.050 g, 0.13 mmol) in MeOH (5 mL) was stirred at
RT
overnight. The solvent was evaporated under reduced pressure and the residue
obtained was
dissolved in diethyl ether (20 mL). The ethereal solution was washed with
water and brine,
dried (MgSO4), and evaporated under reduced pressure. Purification by flash
column
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chromatography on silica gel (20% diethyl ether-hexane) gave the pure compound
18 (0.046
g, 82% yield), as a white solid (m p 57-59 C).
[01961 18 was confirmed as follows: 'H NMR. (500 MHz, CDCI3) 6 7.43 (d, J =
7.5 Hz,
2H), 7.38 (t, J = 7.5 Hz, 2H), 7.32 (t, J = 7.5 Hz IH), 7.08 (d, J = 8.7 Hz,
2H), 6.90 (d, J = 8.7
Hz, 2H), 5.04 (s, 2H), 3.88 (s, 3H), 3.08 (m as t, half of an AA'XX' system, J
= 7.7 Hz, 2H),
2.54 (t, J = 7.7 Hz, 2H), 1.85 (quintet, J = 7.7 Hz, 2H), 1.56 (quintet, J =
7.0 Hz, 2H), 1.46-
1.39 (m, 2H), 1.38-1.30 (m, 4H).
Synthesis of trifluoronethyl ketones (23.1-12 and 24.1-10)
[01971 Trifluoromethyl ketones 23.1-12 and 24.1-10 were synthesized by a
method
depicted in Scheme 5 starting from commercially available 2- or 3- or 4-
(benzyloxy)phenol
(19) and the appropriate w-bromo-n-alkyl acid ethyl ester. 4-Phenoxy-butanoic
acid (21.11)
and 5-phenoxy-pentanoic acid (21.12) were also commercially available
materials.
Compound 24.5 was isolated in its hydrate form.
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Scheme 5
R1 / OH a R ,00 b R OEt t'y' OH
R2 R3 R2 R3 R2 R3
19 20 21
19.1: R1 = OBn, R2 = H, R3 = H 20.1: R1 = OBn, R2 = H, R3 = H, n = 3 21.1: R1
= OBn, R2 = H, R3 = H, n = 3
19.2: R1 = H, R2 = OBn, R3 = H 20.2: R1 = OBn, R2 = H, R3 = H, n = 4 21.2: R1
= OBn, R2 = H, R3 = H, n = 4
19.3: R1 = H, R2 = H, R3 = OBn 203: R1 = OBn, R2 = H, R3 = H, n = 5 21.3: R1 =
OBn, R2 = H, R3 = H, n = 5
20.4: R1 = OBn, R2 = H, R3 = H, n = 6 21.4: R1 = OBn, R2 = H, R3 = H, n = 6
20.5: R1 = H, R2 = OBn, R3 = H, n = 3 21.5: R1 = H, R2 = OBn, R3 = H, n = 3
20.6: R1 = H, R2 = OBn, R3 = H, n = 4 21.6: R1 = H, R2 = OBn, R3 = H, n = 4
20.7: R1 = H, R2 = OBn, R3 = H, n = 5 21.7: R1 = H, R2 = OBn, R3 = H, n = 5
20.8: R1 = H, R2 = H, R3 = OBn, n = 3 21.8: R1 = H, R2 = H, R3 = OBn, n = 3
20.9: R1= H, R2 = H, R3=OBn,n=4 21.9: R1 = H, R2 = H, R3=OBn,n=4
20.10: R1= H, R2 H, R3 = OBn, n = 5 21,10: R1= H, R2= H, R3=OBn,n=5
21.11: R1= H, R2 = H, R3 = H, n = 3
21.12: R1 =H, R2=H, R3= H, n=4
O
1 / O e O
R p d RI Mn \CI n CF3 CF3
R2 R3 R2 R3 R2 R3
22 23 24
22.1: R1 = OBn, R2 = H, R3 = H, n = 3 23.1: R1 = OBn, R2 = H, R3 = H, n = 3
24.1: R1 = OH, R2 = H, R3 = H, n = 3
22.2: R1 = OBn, R2 = H, R3 = H, n = 4 23.2: R1 = OBn, R2 = H, R3 = H, n = 4
24.2: R1 = OH, R2 = H, R3 = H, n = 4
22.3: R1 = OBn, R2 = H, R3 = H, n = 5 23.3: R1 = OBn, R2 = H, R3 = H, n = 5
24.3: R1 = OH, R2 = H, R3 = H, n = 5
22.4: R1 = OBn, R2 = H, R3 = H, n = 6 23.4: R1 = OBn, R2 = H, R3 = H, n = 6
24.4: R1 = OH, R2 = H, R3 = H, n = 6
22.5: R1 = H, R2 = OBn, R3 = H, n = 3 23.5: R1 = H, R2 = OBn, R3 = H, n = 3
24.5*: R1 = H, R2 = OH, R3 = H, n = 3
22.6:R1=H,R2=OBn,R3=H,n=4 23.6:R1=H,R2=OBn,R3=H,n=4 24.6:R1=H,R2=OH,R3=H,n=4
22.7:R1=H,R2=OBn,R3=H,n=5 23.7:R1=H,R2=OBn,R3=H,n=5 24.7:R1=H,R2=OH,R3=H,n=5
22.8: R1 = H , R2=H, R3=OBn, n = 3 23.8: R1 = H , R2=H, R3=OBn, n = 3 24.8: R1
H, R2=H, R3=OH, n=3
22.9:R1=H,R2=H,R3=OBn,n=4 23.9:R1=H,R2=H,R3=OBn,n=4 24.9:R1H,R2=H,R3=OH,n=4
22.10: R1= H, R2 = H, R3 = OBn, n = 5 23.10: R1= H, R2 = H, R3 = OBn, n = 5
24.10: R1= H, R2 = H, R3= OH,n=5
22.11: R1= H, R2 = H, R3 = H, n = 3 23.11: R1= H, R2 = H, R3=H,n=3
22.12: R1= H, R2= H, R3= H,n=4 23.12: R1= H, R2= H, R3=H,n=4
Compound 24.5 was isolated in its hydrate form.
[0198] Reagents and conditions for the steps in Scheme 5 were as follows: Step
a:
K2C03, 18-crown-6, Br-(CH2)õ-COOEt, RT; Strep b: KOH, EtOH/H2O, RT, 80-93%
from
19; Step c: (COCI)2, CH2C12, RT; Step d: (i) pyridine, CF3COOCOCF3, CH2Cl2, -
78 C to
0 C, (ii) H2O, 0 C to RT, 57-63% from 21; Step e: H2, Pd/C, EtOH, RT, 70-97%.
Esters (20)
[0199] A mixture of benzyloxyphenol (19) (1 equiv.), w-bromo-n-alkyl acid
ethyl ester
(1.2 equiv.), potassium carbonate (1.2 equiv.), and 18-crown-6 (Iequiv.) in
anhydrous
acetonitrile was stirred overnight at RT under an argon atmosphere. The
reaction mixture
was evaporated, and the residue was partitioned between water and diethyl
ether. The
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organic phase was separated, washed with brine, dried (MgSO4), and the solvent
was
removed under reduced pressure to leave the crude product (20). This product
contains small
amounts of unreacted w-bromo-n-alkyl acid ethyl ester. It was used in the next
step without
purification. For analytical purposes 20.7 and 20.4 were further purified by
flash column
chromatography (20% diethyl ether-hexane) on silica gel. For a 1H NMR spectrum
and an
alternative method for the preparation of 20.4 see description for the
synthesis of a-keto-
heterocycles.
6-[3-(Benzyloxy)phenoxy]hexanoic acid ethyl ester (20.7)
[0200] Following the procedure described for esters, 6-[3-
(Benzyloxy)phenoxy]hexanoic
acid ethyl ester (20.7) was as a colorless oil.
[0201] 20.7 was confirmed as follows: 1H NMR (500 MHz, CDC13) 6 7.41 (d, J =
7.3 Hz,
2H), 7.36 (t, J = 7.3 Hz, 2H), 7.30 (t, J = 7.3 Hz, 1 H), 7.14 (t, J = 8.2 Hz,
1 H), 6.57-6.52 (m,
2H), 6.49 (dd, J = 8.2 Hz, J = 1.8 Hz, I H), 5.01 (s, 2H), 4.11 (q, J = 7.2
Hz, 2H), 3.91 (t, J =
6.5 Hz, 2H), 2.31 (t, J = 7.5 Hz, 2H), 1.80-1.73 (in, 2H), 1.72-1.64 (in, 2H),
1.51-1.43 (in,
2H), 1.24 (t, J = 7.2 Hz, 3H).
Acids (21)
[0202] A mixture of the crude ester (20) and KOH (1.3 equiv.) in EtOH/H20
(10:1
mixture) was heated under reflux for 3-4 hours. The reaction mixture was
cooled to RT, and
the solvent was removed under reduced pressure. The residue obtained was
dissolved in
water, and the pH was adjusted to 1 using concentrated HCI solution. The
precipitated crude
acid was isolated by filtration and dissolved in ethyl acetate. The resulting
solution was
washed with brine, dried (MgSO4), and the solvent was evaporated to give the
product 21 in
80-93% yield (from 19).
Selected data of synthesized acids (21)
4-j4- Benzyloxy)phenoxy]butanoic acid (21.1)
[0203] According to the procedure described above for acids, 4-[4-
(Benzyloxy)phenoxy]butanoic acid (21.1) was obtained as a white solid with a
melting point
of 125-126 C.
[0204] 21.1 was confirmed as follows: 'H NMR (500 MHz, CDC13) 8 10.95 (br s,
1H),
7.41 (d, J = 7.3 Hz, 2H), 7.37 (t, J = 7.3 Hz, 2H), 7.31 (t, J = 7.3 Hz, 1H),
6.90 (m as d, J =
9.0 Hz, 2H), 6.81 (m as d,J=9.0Hz,2H),5.01(s,2H),3.97(t,J=6.3Hz,2H),2.58(t,J=
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7.5 Hz, 2H), 2.09 (quintet, J = 6.7 Hz, 2H); IR (neat) 2904, 2865, 1704, 1509
em-1.
5-[4-(Benzyloxy)phenoxy]pentanoic acid (21.2)
[0205] According to the procedure described above for acids, 5-[4-
(Benzyloxy)phenoxy]pentanoic acid (21.2) was obtained as a white solid with a
melting point
of 127-128 C.
[0206] 21.2 was confirmed as follows: 'H NMR (500 MHz, CDC13) 6 11.04 (br s,
1H),
7.42 (d, J= 7.3 Hz, 2H), 7.37 (t, J = 7.3 Hz,2H),7.31 (t,J=7.3 Hz,
1H),6.89(d,J=8.9Hz,
2H), 6.81 (d, J = 8.9 Hz, 2H), 5.01 (s, 2H), 3.92 (t, J = 6.4 Hz, 2H), 2.44
(t, J = 7.1 Hz, 2H),
1.85-1.79 (in, 4H); IR (neat) 2954, 2864, 1694, 1509 cm-1.
6-[4-(Benzyloxy)phenoxy]hexanoic acid (21.3)
[0207] According to the procedure described above for acids, 6-[4-
(Benzyloxy)phenoxy]hexanoic acid (21.3) was obtained as a white solid with a
melting point
of 100-101 C.
[0208] 21.3 was confirmed as follows: 'H NMR (500 MHz, CDC13) 6 11.00 (br s,
1H),
7.42(d,J=7.3Hz,2H),7.37(t,J=7.3Hz,2H),7.31(t,J=7.3Hz,1H), 6.89 (d, J= 9.0 Hz,
2H), 6.81 (d, J = 9.0 Hz, 2H), 5.01 (s, 2H), 3.90 (t, J = 6.4 Hz, 2H), 2.39
(t, J = 7.4 Hz, 2H),
1.78 (quintet, J = 6.8 Hz, 2H), 1.71 (quintet, J = 7.5 Hz, 2H), 1.60-1.45 (m,
2H); IR (neat)
2945, 2863, 1693, 1508 cm-1
.
7-[4-(Benz yloxy)phenoxy]heptanoic acid (21.4)
[0209] According to the procedure described above for acids, 7-[4-
(Benzyloxy)phenoxy]heptanoic acid (21.4) was obtained as a white solid with a
melting point
of 118-119 C.
[0210] 21.4 was confirmed as follows: 'H NMR (500 MHz, CDC13) b 11.20 (br s,
1H),
7.42 (d, J = 7.3 Hz, 2H), 7.37 (t, J = 7.3 Hz, 2H), 7.31 (t, J = 7.3 Hz, 1H),
6.89 (d, J = 9.0 Hz,
2H), 6.81 (d, J = 9.0 Hz, 2H), 5.01 (s, 2H), 3.89 (t, J = 6.4 Hz, 2H), 2.36
(t, J = 7.4 Hz, 2H),
1.79-1.72 (m, 2H), 1.70-1.63 (m, 2H), 1.51-1.37 (in, 4H).
4-[3-(Benzyloxy)phenoxy]butanoic acid (21.5)
[0211] According to the procedure described above for acids, 4-[3-
(Benzyloxy)phenoxy]butanoic acid (21.5) was obtained as a white solid with a
melting point
of 76-77 C.
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5-[3-(Benzyloxy)phenoxy]pentanoic acid (21.6)
[0212] According to the procedure described above for acids, 5-[3-
(Benzyloxy)phenoxy]pentanoic acid (21.6) was obtained as a white solid with a
melting. in p
71-72 C.
[0213] 21.6 was confirmed as follows: 'H NMR (500 MHz, CDC13) 6 10.82 (br s,
1H),
7.45 (d, J = 7.3 Hz, 2H), 7.38 (t, J = 7.3 Hz, 2H), 7.32 (t, J = 7.3 Hz, 1 H),
7.17 (t, J = 8.2 Hz,
1H),6.57(dd,.1=8.2Hz,J=2.0Hz, IH),6.54(t,J=2.0Hz, 1H),6.50(dd,J=8.2Hz,J=
2.0 Hz, 1H), 5.04 (s, 2H), 3.95 (t, J = 5.7 Hz, 2H), 2.44 (t, J = 6.7 Hz, 2H),
1.87-1.80 (m, 4H).
6-[3-(Benzvloxy)phenoxy]hexanoic acid (21.7)
[0214] According to the procedure described above for acids, 6-[3-
(Benzyloxy)phenoxy]hexanoic acid (21.7) was obtained as a white solid with a
melting point
of 72-73 C.
[0215] 21.7 was confirmed as follows: 'H NMR (500 MHz, CDC13) b 11.31 (br s,
1H),
7.42 (d, J = 7.3 Hz,2H),7.38 (t, J= 7.3 Hz,2H),7.32(t,J=7.3 Hz,
1H),7.16(t,J=8.2Hz,
1H),6.56(dd,J=8.2Hz,J=1.8Hz, 1H),6.54(t,J=1.8Hz, 1H),6.50(dd,J=8.2Hz,J=
1.8 Hz, 1H), 5.04 (s, 2H), 3.93 (t, J = 6.5 Hz, 2H), 2.39 (t, J = 7.5 Hz, 2H),
1.83-1.75 (in, 2H),
1.74-1.67 (7n, 2H), 1.56-1.48 (m, 2H).
4-[2-(Benzyloxy)phenoxy]butanoic acid (21.8)
[0216] According to the procedure described above for acids, 4-[2-
(Benzyloxy)phenoxy]butanoic acid (21.8) was obtained as a white solid with a
melting point
of 75-76 C.
[0217] 21.8 was confirmed as follows: ' H NMR (500 MHz, CDC13) 8 9.50 (br s, 1
H),
7.44 (d, J = 7.4 Hz, 2H), 7.37 (t, J = 7.4 Hz, 2H), 7.30 (t, J = 7.4 Hz, 1H),
6.95-6.86 (m, 4H),
5.12 (s, 2H), 4.09 (t, J = 5.9 Hz, 2H), 2.61 (t, J = 7.1 Hz, 2H), 2.15
(quintet, J = 6.5 Hz, 2H);
IR (neat) 1693, 1590 cm-'.
5-j2-(Benzyloxy)phenoxylpentanoic acid (21.9)
[0218] According to the procedure described above for acids, 5-[2-
(Benzyloxy)phenoxy]pentanoic acid (21.9) was obtained as a white solid with a
melting point
of 74-75 C.
[0219] 21.9 was confirmed as follows: 1H NMR (500 MHz, CDCI3) 8 11.02 (br s,
1H),
7.44 (d, J = 7.4 Hz, 2H), 7.36 (t, J = 7.4 Hz, 2H), 7.29 (t, J = 7.4 Hz, 1H),
6.95-6.85 (m, 4H),
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5.12 (s, 2H), 4.05 (t, J = 5.9 Hz, 2H), 2.45 (t, J = 7.1 Hz, 2H), 1.92-1.82
(m, 4H).
6-[2-(Benzyloxy)phenoxy]hexanoic acid (21.10)
[0220] According to the procedure described above for acids, 6-[2-
(Benzyloxy)phenoxy]hexanoic acid (21.10) was obtained as a white solid with a
melting
point of 77-78 C.
[0221] 21.10 was confirmed as follows: 1H NMR (500 MHz, CDC13) 6 10.92 (br s,
1H),
7.44 (d, J = 7.3 Hz, 2H), 7.36 (t, J = 7.3 Hz, 2H), 7.29 (t, J = 7.3 Hz, 1 H),
6.95-6.84 (m, 4H),
5.12 (s, 2H), 4.03 (t, J = 6.4 Hz, 2H), 2.36 (t, J = 7.2 Hz, 2H), 1.85
(quintet, J = 6.7 Hz, 2H),
1.71 (quintet, J = 7.3 Hz, 2H), 1.59-1.51 (in, 2H).
Carboxylic acid chlorides (22)
[0222] To a solution of acid (21) (1 equiv.) in anhydrous CH2CI2 at RT, under
an argon
atmosphere was added oxalyl chloride (2 equiv.) over a 2-min period. The
mixture was
stirred for 2 hours, solvent and excess oxalyl chloride were removed under
reduced pressure,
and the crude carboxylic acid chloride (22) was used in the next step without
further
purification.
Trifluoromethyl ketones (23)
[0223] To a solution of carboxylic acid chloride (22) in anhydrous CH2Ch at -
78 C
under an argon atmosphere were added successively trifluoroacetic anhydride (6
equiv.) and
dry pyridine (8 equiv.). The reaction mixture was stirred at -78 C for 2
hours, and then it
was allowed to warm to 0 C and stirred for an additional 2 hours. Water was
added
dropwise, the resulting mixture was warmed to RT, and extracted with CH2Ch.
The organic
layer was washed with brine, dried (MgSO4), and the solvent was evaporated.
Following the
workup, the crude mixture was chromatographed on a silica gel column (eluting
with 30%
diethyl ether-hexane), and the fraction that contains the product was
concentrated and dried in
high vacuum (in the presence of P205) to give compound 23 in 57-63% yield
(from 21).
Selected data of synthesized trifluoromethyl ketones (23)
1,1,1-Trifluoro-5-[4-(benzyloxy)phenoxy]-2-pentanone (23.1)
[0224] According to the procedure described above for trifluoromethyl ketones,
1,1,1-
Trifluoro-5-[4-(benzyloxy)phenoxy]-2-pentanone (23.1) was obtained as a white
solid with a
melting point of 59-61 C.
[0225] 23.1 was confirmed as follows: 'H NMR (500 MHz, CDC13) b 7.41 (d, J =
7.3 Hz,
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2H), 7.37 (t, J = 7.3 Hz, 2H), 7.30 (t, J = 7.3 Hz, 1H), 6.89 (m as d, J = 9.0
Hz, 2H), 6.79 (in
asd,J=9.0Hz,2H),5.01(s,2H),3.96(t,J=5.7Hz,2H),2.93(t,J7.0Hz,2H),2.14
(quintet, J = 6.5 Hz, 2H); IR (neat) 1765, 1509 cm'.
1,1,1-Trifluoro-6-[4-(Benzyloxy)phenoxy]-2-hexanone (23.2)
[0226] According to the procedure described above for trifluoromethyl ketones,
1,1,1-
Trifluoro-6-[4-(Benzyloxy)phenoxy]-2-hexanone (23.2) was obtained as a white
solid with a
melting point of 95.5-96 C.
[0227] 23.2 was confirmed as follows: 'H NMR (500 MHz, CDC13) 8 7.42 (d, J =
7.3 Hz,
2H), 7.38 (t, J = 7.3 Hz, 2H), 7.31 (t, J = 7.3 Hz, I H), 6.90 (d, J = 8.9 Hz,
2H), 6.81 (d, J =
8.9 Hz, 2H), 5.01 (s, 2H), 3.93 (t, J = 6.4 Hz, 2H), 2.82 (t, J = 7.1 Hz, 2H),
1.88 (quintet, J =
7.1 Hz, 2H), 1.81 (quintet, J = 6.6 Hz, 2H); IR (neat) 1759, 1509 cn11
.
1,1,1-Trifluoro-7-[4-(Benzyloxy)phenoxy]-2-heptanone (23.3)
[0228] According to the procedure described above for trifluoromethyl ketones,
1,1,1-
Trifluoro-7-[4-(Benzyloxy)phenoxy]-2-heptanone (23.3) was obtained as a white
solid with a
melting point of 59-60 C.
[0229] 23.3 was confirmed as follows: IR (neat) 1761, 1509 em-1.
1,1.1-Trifluoro-8-[4-(Benzyloxy)phenoxy]-2-octanone (23.4)
[0230] According to the procedure described above for trifluoromethyl ketones,
1,1,1-
Trifluoro-8-[4-(Benzyloxy)phenoxy]-2-octanone (23.4) was obtained as a white
solid with a
melting point of 82-83 C.
[0231] 23.4 was confirmed as follows: ' H NMR (500 MHz, CDC13) 8 7.42 (d, J =
7.3 Hz,
2H), 7.3 8 (t, J = 7.3 Hz, 2H), 7.31 (t, J = 7.3 Hz, 1 H), 6.89 (d, J = 8.9
Hz, 2H), 6.81 (d, J =
8.9 Hz, 2H), 5.01 (s, 2H), 3.90 (t, J = 6.4 Hz, 2H), 2.73 (t, J = 7.1 Hz, 2H),
1.80-1.67 (in, 4H),
1.52-1.45 (m, 2H), 1.44-1.36 (m, 2H).
1,1,1-Trifluoro-5-r3-(Benzyloxy)phenoxy]-2-pentanone (23.5)
[0232] According to the procedure described above for trifluoromethyl ketones,
1,1,1-
Trifluoro-5-[3-(Benzyloxy)phenoxy]-2-pentanone (23.5) was obtained as a
colorless viscous
oil.
[0233] 23.5 was confirmed as follows: 'H NMR (500 MHz, CDC13) 8 7.42 (d, J =
7.3 Hz,
2H), 7.38 (t, J = 7.3 Hz, 2H), 7.31 (t, J = 7.3 Hz, IH), 7.16 (t, J = 8.2 Hz,
1H), 6.58 (dd, J =
8.2 Hz, J = 2.0 Hz, I H), 6.52 (t, J = 2.0 Hz, I H), 6.48 (dd, J = 8.2 Hz, J =
2.0 Hz, I H), 5.03
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(s, 2H), 3.96 (t, J = 5.9 Hz, 2H), 2.92 (t, J = 6.9 Hz, 2H), 2.14 (quintet, J
= 6.5 Hz, 2H); IR
(neat) 1763, 1591 cm-'.
1,1,1-Trifluoro-6-[3-(Benzyloxy)phenoxy]-2-hexanone (23.6)
[0234] According to the procedure described above for trifluoromethyl ketones,
1,1,1-
Trifluoro-6-[3-(Benzyloxy)phenoxy]-2-hexanone (23.6) was obtained as a
colorless viscous
oil.
[0235] 23.6 was confirmed as follows: 'H NMR (500 MHz, CDC13) b 7.42 (d, J =
7.3 Hz,
2H), 7.38 (t, J = 7.3 Hz, 2H), 7.32 (t, J = 7.3 Hz, 1H), 7.17 (t, J = 8.2 Hz,
1 H), 6.58 (dd, J =
8.2 Hz, J = 2.0 Hz, 1H), 6.53 (t, J = 2.0 Hz, IH), 6.49 (dd, J = 8.2 Hz, J =
2.0 Hz, 1H), 5.04
(s, 2H), 3.96 (t, J = 5.9 Hz, 2H), 2.81 (t, J = 6.8 Hz, 2H), 1.91-1.78 (m,
4H).
1,1,1-Trifluoro-7-[3-(Benzyloxy)phenoxy]-2-heptanone (23.7)
[0236] According to the procedure described above for trifluoromethyl ketones,
1,1,1-
Trifluoro-7-[3-(Benzyloxy)phenoxy]-2-heptanone (23.7) was obtained as a
colorless viscous
oil.
1,1,1-Trifluoro-5-[2-(Benzyloxy)phenoxy]-2-pentanone (23.8)
[0237] According to the procedure described above for trifluoromethyl ketones,
1,1,1-
Trifluoro-5-[2-(Benzyloxy)phenoxy]-2-pentanone (23.8) was obtained as a white
solid with a
melting point of 50-51 C.
[0238] 23.8 was confirmed as follows: 'H NMR (500 MHz, CDC13) b 7.42 (d, J =
7.4 Hz,
2H), 7.36 (t, J = 7.4 Hz, 2H), 7.30 (t, J = 7.4 Hz, IH), 6.96-6.89 (m, 4H),
5.09 (s, 2H), 4.06 (t,
J = 5.9 Hz, 2H), 2.98 (t, J = 7.0 Hz, 2H), 2.16 (quintet, J = 6.5 Hz, 2H); IR
(neat) 1763, 1593
cm'.
1.1.1-Trifluoro-6-[2-(Benzyloxy)phenoxy]-2-hexanone (23.9)
[0239] According to the procedure described above for trifluoromethyl ketones,
1,1,1-
Trifluoro-6- [2 -(B enzylo xy)phenoxy] -2 -hex anone (23.9) was obtained as a
colorless viscous
oil.
[0240] 23.9 was confirmed as follows: 'H NMR (500 MHz, CDC13) 8 7.42 (d, J =
7.4 Hz,
2H), 7.35 (t, J = 7.4 Hz, 2H), 7.29 (t, J = 7.4 Hz, 1 H), 6.93 (d, J = 7.4 Hz,
1 H), 6.91-6.86 (m
and t overlapping, especially 6.90, t, J = 3.9 Hz, 3H), 5.10 (s, 2H), 4.04 (t,
J = 5.9 Hz, 2H),
2.80 (t, J = 6.9 Hz, 2H), 1.93-1.82 (m, 4H).
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1,1,1-Trifluoro-7-[2-(Benzyloxy)phenoxy]-2-heptanone (23.10)
[0241] According to the procedure described above for trifluoromethyl ketones,
1,1,1-
Trifluoro-7-[2-(Benzyloxy)phenoxy]-2-heptanone (23.10) was obtained as a white
solid with
a melting point 31-32 C.
[0242] 23.10 was confirmed as follows: 'H NMR (500 MHz, CDC13) b 7.43 (d, J =
7.3
Hz, 2H), 7.36 (t, J = 7.3 Hz, 2H), 7.30 (t, J = 7.3 Hz, 1H), 6.95-6.85 (m,
4H), 5.11 (s, 2H),
4.03 (t, J = 6.4 Hz, 2H), 2.70 (t, J = 7.1 Hz, 2H), 1.86 (quintet, J = 6.7 Hz,
2H), 1.75 (quintet,
J = 7.3 Hz, 2H), 1.59-1.50 (m, 2H).
1,1,1-Trifluoro-5-phenoxv-2-pentanone (23.11)
[0243] According to the procedure described above for trifluoromethyl ketones,
1,1,1-
Trifluoro-5-phenoxy-2-pentanone (23.11) was obtained as a colorless viscous
oil.
[0244] 23.11 was confirmed as follows: 'H NMR (500 MHz, CDC13) 6 7.28 (t, J =
7.4
Hz, 2H), 6.95 (t, J = 7.4 Hz, 1H), 6.87 (d, J = 7.4 Hz, 2H), 4.00 (t, J = 5.8
Hz, 2H), 2.95 (t, J =
7.0 Hz, 2H), 2.17 (quintet, J = 6.4 Hz, 2H); 13C NMR (126 MHz, CDC13) 6 191.6
(q, J = 35
Hz, C=O), 158.9, 129.9, 121.4, 116.0 (q, J = 292 Hz, CF3), 114.8, 66.1, 33.5,
22.8; IR (neat)
1763, 1601, 1588, 1498 cm'; mass spectrum m/z (relative intensity) 232 (M+,
25), 139 (24),
94(100), 77 (16), 69 (27). Exact mass calculated for C,,Hi,O2F3; 232.0711;
found,
232.0714.
1,1,1-Trifluoro-6-phenoxv-2-hexanone (23.12)
[0245] According to the procedure described above for trifluoromethyl ketones,
1,1,1-
Trifluoro-6-phenoxy-2-hexanone (23.12) was obtained as a white solid with a
melting point
of 50-51 C.
[0246] 23.12 was confirmed as follows: 'H NMR (500 MHz, CDC13) 8 7.28 (t, J =
7.4
Hz,2H),6.94(t,J=7.4Hz,IH),6.88(d,J=7.4Hz,2H),3.98(t,J=5.9 Hz,2H),2.83(t,J=
6.7 Hz, 2H), 1.95-1.80 (m, 4H); '3C NMR (126 MHz, CDC13) 6 191.7 (q, J = 35
Hz, C=O),
159.2, 129.9, 121.2, 116.0 (q, J = 291 Hz, CF3), 114.8, 67.5, 36.4, 28.6,
19.8; 1R (neat) 1759,
1601, 1585, 1500 cm-1.
Trifluoromethyl ketones (24)
[0247] To a solution of trifluoromethyl ketone (23) (1 equiv.) in EtOH was
added 10%
Pd/C (7% w/w), and the resulting suspension was stirred vigorously under
hydrogen
atmosphere, overnight at RT. The catalyst was removed by filtration through
Celite, and the
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filtrate was evaporated under reduced pressure. The residue obtained was
chromatographed
on a silica gel column (eluting with 60% diethyl ether-hexane), and the
fraction that contains
the product was concentrated and dried in high vacuum (in the presence of
P205) to give
compound 24 in 70-97% yield. Especially in case of compound 24.5 the hydrate
was isolated
in 80% yield.
Selected data of synthesized trifluoromethyl ketones (24)
1,1,1-Trifluoro-5-[4-(hydroxy)phenoxy]-2-pentanone (24.1)
[0248] According to the procedure described above for trifluoromethyl ketones
(24),
1,1,1-Trifluoro-5-[4-(hydroxy)phenoxy]-2-pentanone (24.1) was obtained as as a
colorless
viscous oil.
[0249] 24.1 was confirmed as follows: ' H NMR (500 MHz, CDC13) b 6.76 (in as
br s,
4H), 4.51 (br s, 1 H), 3.95 (t, J = 5.8 Hz, 2H), 2.95 (t, J = 7.0 Hz, 2H),
2.15 (quintet, J = 6.5
Hz, 2H); 13C NMR (126 MHz, CDC13) 6 191.5 (q, J = 35 Hz, C=O), 152.7, 149.8,
116.2,
115.7, 115.6 (q, J = 292 Hz, CP3), 66.7, 33.2, 22.5; IR (neat) 3379 br, 1763,
1509 cm-1.
1,1,1-Trifluoro-6-[4-(hydroxy)phenoxy]-2-hexanone (24.2)
[0250] According to the procedure described above for trifluoromethyl ketones
(24),
1,1,1-Trifluoro-6-[4-(hydroxy)phenoxy]-2-hexanone (24.2) was obtained as a
white solid
with a melting point of 63-64 C.
[0251] 24.2 was confirmed as follows: 'H NMR (500 MHz, CDCI3) 8 6.76 (m as br
s,
4H), 4.57 (br s, I H), 3.92 (t, J = 6.4 Hz, 2H), 2.82 (t, J = 7.1 Hz, 2H),
1.88 (quintet, J = 7.1
Hz, 2H), 1.81 (quintet, J = 6.6 Hz, 2H); IR (neat) 3398 br, 1754, 1509 cm-1.
1,1,1-Trifluoro-7-[4-(h d~Y)phenoxy]-2-heptanone (24.3)
[0252] According to the procedure described above for trifluoromethyl ketones
(24),
1,1,1-Trifluoro-7-[4-(hydroxy)phenoxy]-2-heptanone (24.3) was obtained as a
colorless
viscous oil.
[0253] 24.3 was confirmed as follows: IR (neat) 3386 br, 1762, 1509 cm-1.
1,1,1-Trifluoro-8-[4-(hydroxy)phenoxy]-2-octanone (24.4)
[0254] According to the procedure described above for trifluoromethyl ketones
(24),
1,1,1-Trifluoro-8-[4-(hydroxy)phenoxy]-2-octanone (24.4) was obtained as a
white solid with
a melting point of 61-62 C.
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[0255] 24.4 was confirmed as follows: 'H NMR (500 MHz, CDC13) 6 6.77 (in as d,
J =
9.1 Hz, 2H), 6.75 (m as d, J = 9.1 Hz, 2H), 4.40 (br s, 1 H), 3.89 (t, J = 6.4
Hz, 2H), 2.73 (t, J
= 7.1 Hz, 2H), 1.80-1.67 (in, 4H), 1.52-1.45 (m, 2H), 1.44-1.36 (m, 2H).
1,1.1-Trifluoro-2.2-dih d5-[3-(hydroxy)phenoxylpentane (24.5)
[0256] According to the procedure described above for trifluoromethyl ketones
(24),
1,1,1-Trifluoro-2,2-dihydroxy-5-[3-(hydroxy)phenoxy]pentane (24.5) was
obtained as a
white solid with a melting point of 76-77 C.
[0257] 24.5 was confirmed as follows: 'H NMR (500 MHz, CDC13/DMSO-d6) 6 8.53
(br
s, exchange with D2O, 1H), 7.06 (t, J = 8.2 Hz, 1H), 6.47-6.42 (m, 2H), 6.39
(dd, J = 8.2 Hz,
J = 1.9 Hz, 1H), 5.49 (br s, exchange with D7O, 2H), 3.99 (t, J = 6.1 Hz, 2H),
2.05 (m, 2H),
1.95 (t, J = 7.1 Hz, 2H); IR (neat) 3300 br, 1605 cm'.
1,1,1-Trifluoro-6-[3-(h d~y)phenoxy]-2-hexanone (24.6)
[0258] According to the procedure described above for trifluoromethyl ketones
(24),
1,1,1-Trifluoro-6-[3-(hydroxy)phenoxy]-2-hexanone (24.6) was obtained as a
colorless
viscous oil.
[0259] 24.6 was confirmed as follows: 'H NMR (500 MHz, CDC13) 6 7.11 (t, J =
8.2 Hz,
1 H), 6.46 (dd, J = 8.2 Hz, J = 2.2 Hz, 1 H), 6.42 (dd, J = 8.2 Hz, J = 2.2
Hz, 1 H), 6.39 (t, J =
2.2 Hz, 1H), 5.19 (br s, 1H), 3.94 (t, J = 5.9 Hz, 2H), 2.81 (t, J = 6.8 Hz,
2H), 1.90-1.77 (in,
4H).
1,1,1-Trifluoro-7-[3-(hydroxy)phenoxyl-2-heptanone (24.7)
[0260] According to the procedure described above for trifluoromethyl ketones
(24),
1,1,1-Trifluoro-7-[3-(hydroxy)phenoxy]-2-heptanone (24.7) was obtained as an
orange
viscous oil.
1,1,1-Trifluoro-5-[2-(hydroxy)phenoxy]-2-pentanone (24.8)
[0261] According to the procedure described above for tri fluorolethyl ketones
(24),
1,1,1-Trifluoro-5-[2-(hydroxy)phenoxy]-2-pentanone (24.8) was obtained as a
colorless
viscous oil.
[0262] 24.8 was confirmed as follows: 'H NMR (500 MHz, CDC13) 6 6.95 (d, J =
7.7 Hz,
1 H), 6.89 (m as quintet, J = 3.9 Hz, 1 H), 6.83 (d, J = 4.2 Hz, 2H), 5.52 (br
s, 1 H), 4.11 (t, J =
6.0 Hz, 2H), 2.96 (t, J = 6.9 Hz, 2H), 2.23 (quintet, J = 6.5 Hz, 2H).
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1,1,1-Trifluoro-6-[2-(hydroxy)phenoxy] -2-hexanone (24.9)
[0263] According to the procedure described above for trifluoromethyl ketones
(24),
1, 1, 1 -Trifluoro-6-[2-(hydroxy)phenoxy] -2-hexanone (24.9) was obtained as a
white solid
with a melting point of 51-52 C.
[0264] 24.9 was confirmed as follows: 1H NMR (500 MHz, CDC13) 6 6.94 (d, J =
7.7 Hz,
1 H), 6.90-6.86 (m, 1 H), 6.85-6.82 (in, 2H), 5.60 (br s, 1 H), 4.07 (t, J =
5.7 Hz, 2H), 2.83 (t, J
= 6.3 Hz, 2H), 1.94-1.84 (in, 4H).
1,1,1-Trifluoro-7-12-(hydroxy)phenoxy]-2-heptanone (24.10)
[0265] According to the procedure described above for trifluoromethyl ketones
(24),
1,1,1-Trifluoro-7-[2-(hydroxy)phenoxy]-2-heptanolie (24.10) was obtained as a
white semi-
solid.
[0266] 24.10 was confirmed as follows: 'H NMR (500 MHz, CDC13) b 6.84 (d, J =
7.3
Hz, 1H), 6.80-6.72 (m, 3H), 5.58 (br s, 1H), 3.95 (t, J = 6.4 Hz, 2H), 2.66
(t, J = 7.1 Hz, 2H),
1.75 (quintet, J = 6.7 Hz, 2H), 1.66 (quintet, J = 7.3 Hz, 2H), 1.46-1.38 (m,
2H).
Synthesis of Trifluoromethyl Ketones (27)
[0267] Trifluoromethyl ketones (27.1-4) were synthesized by a method depicted
in
Scheme 6. 4-Phenyl-butyric acid (25.1), 5-phenyl-pentanoic acid (25.2), 6-
phenyl-hexanoic
acid (25.3) and 5-(4-methoxy-phenyl)-pentanoic acid (25.4) were commercially
available
starting materials.
Scheme 6
0 0 0
- a - b -
R n OH R / CI R , CF3
25 26 27
25.1: R = H, n = 3 26.1:R=H,n=3 27.1: R = H, n = 3
25.2: R = H, n = 4 26.2: R = H, n = 4 27.2:R=H,n=4
25.3:R=H,n=5 26.3: R = H, n = 5 27.3: R = H, n = 5
25.4: R=OMe,n4 26.4: R=OMe,n=4 27.4: R = OMe, n = 4
Reagents and conditions for the steps in Scheme 6 were as follows: Step a:
(COCI)2, CH7Ch,
RT; Step b: (i) pyridine, CF3COOCOCF3, CH,C17, -78 C to 0 C, (ii) H2O, 0 C to
RT, 61-63%
from 25.
[0268] The synthesis of compounds 27 was carried out analogous to the
preparation of
compounds 23.
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Selected data of synthesized Trifluoromethyl Ketones 27
1.1,1-Trifluoro-5-phenyl-2-penltanone (27.1)
[0269] 27.1 was synthesized as a colorless viscous oil.
[0270] 27.1 was confirmed as follows: IR (neat) 1762, 1604, 1498, 1454, 1403
cm -1.
1, 1, 1 -Trifluoro-6-phenyl-2-hexanone (27.2)
[0271] 27.2 was synthesized as a colorless viscous oil.
[0272] 27.2 was confirmed as follows: 'H NMR (500 MHz, CDC13) 6 7.27 (t, J =
7.5 Hz,
2H), 7.17 (t, J = 7.5 Hz, 1H), 7.15 (d, J = 7.5 Hz, 2H), 2.70 (t, J = 7.2 Hz,
2H), 2.63 (t, J = 7.7
Hz, 2H), 1.76-1.62 (m, 4H); 13C NMR (126 MHz, CDC13) 6 191.7 (q, J = 35 Hz,
C=O),
142.0, 128.8, 128.7, 126.3, 116.0 (q, J = 292 Hz, CF3), 36.6, 35.8, 30.8,
22.4; IR (neat) 1763,
1604, 1497, 1454, 1404 cm-'.
1,1,1-Trifluoro-7-phenyl-2-heptanone (27.3)
[0273] 27.3 was synthesized as a colorless viscous oil.
[0274] 27.3 was confirmed as follows: 'H NMR (500 MHz, CDC13) 8 7.27 (t, J =
7.5 Hz,
2H), 7.18 (t, J = 7.5 Hz, 1 H), 7.16 (d, J = 7.5 Hz, 2H), 2.69 (t, J = 7.2 Hz,
2H), 2.61 (t, J = 7.7
Hz, 2H), 1.70 (quintet, J = 7.6 Hz, 2H), 1.64 (quintet, J = 7.6 Hz, 2H), 1.37
(quintet, J = 7.7
Hz, 2H); IR (neat) 1763, 1604, 1497, 1454, 1402 cm-1; mass spectrum m/z
(relative intensity)
244 (M+, 21), 175 (8), 117 (20), 91 (100), 77 (6). Exact mass calculated for
C13H15OF3j
244.1075; found, 244.1073.
1,1,1-Trifluoro-6-(4-methoxy-phenyl)-2-hexanone (27.4)
[0275] 27.4 was synthesized as a colorless viscous oil.
[0276] 27.4 was confirmed as follows: 'H NMR (500 MHz, CDCI3) 8 7.07 (d, J =
8.4 Hz,
2H), 6.82 (d, J = 8.4 Hz, 2H), 3.77 (s, 3H), 2.71 (t, J = 6.9 Hz, 2H), 2.58
(t, J = 7.4 Hz, 2H),
1.70 (quintet, J = 7.1 Hz, 2H), 1.62 (quintet, J = 6.8 Hz, 2H); IR (neat)
1763, 1612, 1584,
1512 cm-1.
Synthesis of Trifluoromethyl Ketones 30 and 35
[0277] Trifluoromethyl ketones (30 and 35) were synthesized by a method
depicted in
Scheme 7. 3-(Methoxycarbonyl)phenylboronic acid, 3-benzyloxyphenylboronic acid
and 3-
benzyloxybromobenzene (28) were commercially available starting materials
while (3-
bromophenyl)acetic acid methyl ester (31) was synthesized from commercially
available 3-
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bromophenylacetic acid following a method disclosed in Luning et al., Eur. J.
Org. Chern.
(2002) 3294-3303.
Scheme 7
Br COOMe 0 CF3
OBn
28 29 OBn 30 OBn
O O
COOMe COOMe COOH
CI CF3
31 32 OBn 33 OBn 34 OBn 35 OBn
[0278] Reagents and conditions for the steps in Scheme 7 were as follows:
Step a: 3-(methoxycarbonyl)phenylboronic acid, Ba(OH2), Pd(PPh3)4, DME/H2O,
microwave, see Luning text, 50%; Step b: TMS-CF3, TBAF, PhCH3, N2, -78 C to
RT, 18
hours, 65%; Step c: 3-benzyloxyphenylboronic acid, Ba(OH,), Pd(PPh3)4,
DME/H,O,
microwave, see Luning text, 48%; Step d: KOH, EtOH/H2O, 50 C, 2 hours; Step e:
(COCI)2,
CH2C12, RT, 2 hours; Step f: (i) CF3COOCOCF3, pyridine, CH2C12, 0 C to RT,
(ii) H2O, 0 C
to RT, 37% from 32.
3'-Benzyloxy-biphenyl-3-carboxylic acid methyl ester (29)
[0279] A degassed mixture of 3-benzyloxy-phenyl bromide (28) (0.176 g, 0.67
mmol), 3-
methoxycarbonylphenylboronic acid (0.18 g, 1 mmol), barium hydroxide (0.25 g,
1.47
mmol), Pd(PPh3)4 (0.077 g, 0.067 mmol), DME (5 mL) and H2O (3 ml-) was
microwaved
with vigorous stirring using a CEM-discover system (ram time: 2min, hold time:
5min,
temperature: 120 C, pressure: 200 psi, power: 250 W). The crude reaction
mixture filtered
through a plug of celite and concentrated in v vacuo. The residue obtained was
purified by
flash column chromatography (25% diethyl ether-hexane) to give the title
compound (29)
(0.118 g, 60% yield) as a viscous liquid.
[0280] 29 was confirmed as follows: 'H NMR (500 MHz, CDC13) 6 8.27 (t, J = 1.5
Hz,
I H), 8.20 (dd, J = 8.0 Hz, J = 1.5 Hz, I H), 7.76 (dd, J = 8.0 Hz, J = 2.0
Hz, I H), 7.50 (t, J =
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8.0 Hz, 1 H), 7.47 (d, J = 7.5 Hz, 2H), 7.42-7.32 (m, 4H), 7.25-7.22 (m, 2H),
7.00 (dd, J = 8.2
Hz, J = 2.0 Hz, I H), 5.13 (s, 2H), 3.95 (s, 3H).
1,1,1-Trifluoro-2-(3-benzyloxy-biphenyl-3-yl)-2-ethanone (30)
[02811 A solution of 29 (0.1 g, 0.314 mmol) in anhydrous toluene (5 mL) was
cooled to -
78 C, under nitrogen, and trifluoromethytrimethylsilane (62.5 mg, 0.44 mmol)
was added.
The mixture was stirred for 15 min at -78 C, a 1 M anhydrous solution of
tetrabutyl ammonium fluoride in THE (0.026 ml, 0.026 minol) was added and the
resultant
mixture was gradually warmed to RT. After stirring for 12 hours at RT, the
reaction mixture
was diluted with 4 N HCl solution (2 mL) and stirred for an additional 2 hour
period. The
organic layer was separated and the aqueous layer was extracted with diethyl
ether (20 mL).
The combined organic layer was washed with aqueous saturated NaHCO3 solution
(5 mL)
and brine, dried (MgSO4), and concentrated under reduced pressure. The residue
was
purified by flash column chromatography on silica gel (25% diethyl ether-
hexane) and the
fraction that contains the product (30) and its hydrate form (2:1 ratio by 1 H
NMR) was
concentrated and dried in high vacuum (in the presence of P205) to give pure
compound (30)
(0.0876 g, 76% yield) as a viscous liquid.
[02821 30 was confirmed as follows: 'H NMR (500 MHz, CDC13) 6 8.26 (s, 1H),
8.04 (d,
J = 7.5 Hz, I H), 7.90 (d, J = 8.0 Hz, I H), 7.61 (t, J = 7.5 Hz, I H), 7.47
(d, J = 8.0 Hz, 2H),
7.44-7.38 (m, 3H), 7.3 (t, J = 7.2 Hz, 1H), 7.22-7.20 (m, 2H), 7.03 (dd, J =
8.0 Hz, J = 2.5 Hz,
I H), 5.08 (s, 2H).
2-(3-Benzyloxy-biphenyl-3-yl)-acetic acid methyl ester (32)
[02831 2-(3-Benzyloxy-biphenyl-3-yl)-acetic acid methyl ester (32) was
synthesized
following the procedure described for the preparation of 29 using 3-bromo-
phenyl acetic acid
methyl ester (31) (0.31g, 1.35 mmol), 3-benzyloxy-phenyl boronic acid (0.45 g,
2 mmol),
barium hydroxide (0.5 (y, 3 mmol) and Pd(PPh3)4 (0.15 g, 0.13 mmol), in DME
(10
mL)/water (4 mL). Purification by flash column chromatography on silica gel
gave pure
compound (32) (0.22 g, 49% yield) as a white solid (melting point 50-52 C).
[0284] 32 was confirmed as follows: 1H NMR (500 MHz, CDC13) 8 7.49-7.45 (m,
4H),
7.42-7.32 (m, 5H), 7.27 (d, J = 7.0 Hz, 1 H), 7.21 (t, J = 2.5 Hz, 1 H) 7.19
((dd, J = 7.5 Hz, J =
1.0 Hz, 1 H), 6.97 (dd, J = 8.0 Hz, J = 2.5 Hz 1 H), 5.1 (s, 2H), 3.71 (s,
3H), 3.69 (s, 2H).
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2-(3-Benzyloxy-biphenyl-3-yl)-acetic acid (33)
[0285] A mixture of 26 (0.1 g, 0.3 mmol) and KOH (0.08 g, 1.2 mmol) in wet
EtOH (5
mL) was heated at 50 C, under nitrogen for 2 hours. The reaction mixture was
cooled to RT,
and the solvent evaporated under reduced pressure. The residue obtained was
dissolved in
water (5 mL) and the pH was adjusted to 1 using 5% aqueous HCI solution (2
mL). The
precipitated crude acid was isolated by filtration and dissolved in ethyl
acetate. The resulting
solution was washed with brine, dried (MgSO4), and concentrated under reduced
pressure to
give 33 as a white solid (0.087 g, 91%), which was used in the next step
without further
purification.
1,1,1-Trifluoro-3-(3-benzyloxy-biphenyl-3-yl)-2-propanone (35)
[0286] To a solution of acid (33) (0.08 g, 0.25 mmol) in anhydrous CH2CI2 at
RT, under
nitrogen, was added oxalyl chloride (0.25 mL, 0.5 mmol) over a 2-min period.
The mixture
was stirred for 2 hours, solvent and excess oxalyl chloride were removed under
reduced
pressure, and the crude carboxylic acid chloride (34) was used in the next
step without further
purification.
[0287] To a solution of 34 in anhydrous CH2Ch at 0 C under a nitrogen
atmosphere were
added successively trifluoroacetic anhydride (1 mL, 1.5 mmol) and dry pyridine
(0.16 mmol,
0.16 mL). The reaction mixture was stirred at 0 C for 10 min, and then it was
allowed to
warm to RT and stirred for an additional 2 hour period. Water was added
dropwise at 0 C,
the resulting mixture was warmed to RT, and extracted with CH2CI2. The organic
layer was
washed with dilute aqueous HC1 solution, and saturated aqueous NaHCO3
solution, dried
(MgSO4) and the solvent was evaporated. Following the workup, the crude
mixture was
chromatographed on a silica gel column (eluting with 30% diethyl ether-hexane)
to give
compound (35) (0.033 g, 36% yield) as a viscous liquid.
[0288] 35 was confirmed as follows: 'H NMR (500 MHz, CDC13) 6 7.56 (d, J = 8.0
Hz,
1H), 7.49 (d, J = 7.0 Hz, 2H), 7.47-7.41 (m, 4H), 7.40-7.35 (m, 3H), 7.23-7.19
(in, 3H), 7.03
(dd, J = 8.0 Hz, J = 2.5 Hz, 1H), 5.15 (s, 2H), 4.01 (s, 2H).
Synthesis of Trifluoromethyl ketones 39.1-4 and 40.1, 40.3
[0289] Trifluoromethyl ketones (39.1-4 and 40.1, 40.3) (shown in Scheme 8)
were
synthesized by a method depicted in Scheme S. Resorcinol dimethyl ether 36.1
and 4'-
bromo-2,2,2-trifluoroacetophenone were commercially available starting
materials while
olivetol dimethyl ether (36.2) was synthesized following a method disclosed in
Nikas, et al.
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(2002) Synth. Commniun., 32:1751 and Nikas, et al. (2002) J. Labelled Cornpd.
Radiopharni.,
45:1065. The resorcinol dimethyl ethers (36.3 and 36.4) were synthesized by
methylation of
commercially available 4-hexylresorcinol and 4,6-dichlororesorcinol
respectively.
Scheme 8
R5 R5
R4 a for 36.1 X R4
J or
b for 36.2, 36.3, 36.4
R1 R3 R1 R3
R2 R2
36 37
36.1: R1 = We, R2 = H, R3 = DMH, R4 = H, R5 = We 37.1: R1 = We, R2 = H, R3 =
DMH, R4 = H, R5 = OMe, X = Br
36.2: R1 = OMe, R2 = H, R3 = n-pentyl, R4 = H, R5 = We 37.2: R1 = OMe, R2 = H,
R3 = n-pentyl, R4 = H, R5 = OMe, X = H
36.3: R1 = OMe, R2 = H, R3 = H, R4 = n-hexyl, R5 = We 37.3: R1 = OMe, R2 = H,
R3 = H, R4 = n-hexyl, R5 = We, X = H
36.4: R1 = CI, R2 = OMe, R3 = H, R4 = OMe, R5 = CI 37.4: R1 = CI, R2 = We, R3
= H, R4 = OMe, R5 = CI, X = H
R5
c for 37.1 (HO)2B CR4
or
d for 37.2, 37.3, 37.4 I e
R1 R3
R2
38
38.1: R1 = OMe, R2 = H, R3 = DMH, R4 = H, R5 = OMe
38.2: R1 = We, R2 = H, R3 = n-pentyl, R4 = H, R5 = OMe
38.3: R1 = OMe, R2 = H, R3 = H, R4 = n-hexyl, R5 = We
38.4: R1 = CI, R2 = OMe, R3 = H, R4 = OMe, R5 = CI
0 0
F C R f for 39.1 F C R
3 5 or 3 5
R4 g for 39.3 Ra
R1 R3 R1 R3
2 2
39 40
39.1: R1 = We, R2 = H, R3 = DMH, R4 = H, R5 = We 40.1: R1 = OH, R2 = H, R3 =
DMH, R4 = H, R5 = OH
39.2: R1 = We, R2 = H, R3 = n-pentyl, R4 = H, R5 = We 40.3: R1 = OH, R2 = H,
R3 = H, R4 = n-hexyl, R5 = OMe
39.3: R1 = We, R2 = H, R3 = H, R4 = n-hexyl, R5 = We
39.4: R1 = CI, R2 = OMe, R3 = H, R4 = OMe, R5 = CI
D M H [0290] Reagents and conditions for the steps in Scheme 8 were as
follows: Step a: Br,,
18-crown-6, CH,C12, RT, 20 min, 97%; Step b: Mel, K2C03, DMF, RT, 3-5 hours,
83-95%;
Step c (1) n-BuLi, THF, -78 C, 15 min, (ii) B(OMe)3, -78 C to RT, 12 hours
then aqueous
HCI, 83%; Step d: (1) n-BuLi, THF, -78 C to -10 C, 2.5-7.5 hours, (ii)
B(OMe)3, -78 C to
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RT, overnight then aqueous HCl, 75-85%; Step e: 4'-bromo-2,2,2-
trifluoroacetophenone,
Pd(PPh3)4, Ba(OH)2'8H2O DME/H2O, microwave, 1150C, 300 W. 4-6 min, 63-78%;
Step f:
BBr3, CH2CI7, -78 C to RT, 4 hours, 68%; Step g: n-1314NI, BC13, CH2Cl2, -78 C
to 0 C, 2
hours, 68%.
2-Bromo-5-(1,1-dimethylheptyl)-1,3-dimethoxybenzene (37.1)
[0291] To a vigorously stirred solution of 36.1 (2.09 g, 7.93 mmol) and 18-
crown-6 in
methylene chloride (70 mL) at RT was added bromine dropwise (0.43 mL, 8.30
mmol).
Stirring was continued for 20 min, and the reaction mixture was successively
washed with
10% sodium thiosulphate, a saturated sodium bicarbonate solution, and brine.
The organic
layer was dried over MgSO4, and evaporated, and the crude oil was purified by
flash column
chromatography (3% diethyl ether in hexane) to afford the title compound in
97% yield (2.66
g) as a colorless oil.
[0292] 37.1 was confirmed as follows: 'H NMR (500 MHz, CDC13) 6 6.54 (s, 2H),
3.90
(s, 6H), 1.58 (m, 2H), 1.29 (s, 6H), 1.25-1.19 (m, 6H), 1.05 (m, 2H), 0.85 (t,
J = 6.9 Hz, 3H).
Intermediates 37.2, 37.3 and 37.4
[0293] A mixture of resorcinol (36.2 or 36.3 or 36.4) (1 equiv.), methyl
iodide (2.2
equiv.) and potassium carbonate (2.5 equiv.) in anhydrous dimethylformamide
was stirred for
3-5 hours at RT under an argon atmosphere. The reaction mixture was diluted
with water and
extracted with ethyl acetate. The organic phase was washed with water, brine,
dried
(MgSO4), and the solvent was removed under reduced pressure. The residue was
purified by
flash column chromatography on silica gel (diethyl ether-hexane) to give the
product in 83-
95% yields.
Selected data of synthesized intermediates 37.2 and, 37.3
1,3-Dimethoxy-5-pentylbenzene (37.2)
[0294] 37.2 was confirmed as follows: 'H NMR (500 MHz, CDC13) 6 6.34 (d, J =
2.0 Hz,
2H), 6.29 (t, J = 2.0 Hz, 1H), 3.77 (s, 6H), 2.54 (t, J = 7.2 Hz, 2H), 1.64-
1.57 (m, 2H), 1.38-
1.27 (m, 4H), 0.89 (t, J = 7.3 Hz, 3H).
1,3-Dimethoxy-4-hexylbenzene (37.3)
[0295] 37.3 was confirmed as follows: 'H NMR (500 MHz, CDC13) b 7.02 (d, J =
8.5 Hz,
I H), 6.43 (d, J = 2.5 Hz, I H), 6.40 (dd, J = 8.5 Hz, J = 2.5 Hz, I H), 3.78
(s, 3H), 3.77 (s, 3H),
2.52 (t, J = 7.5 Hz, 2H), 1.56-1.50 (m, 2H), 1.36-1.25 (m, 6H), 0.88 (t, J =
7.0, 3H).
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2,6-Dimethoxy-4-(2-methyloctan-2-yl)phenylboronic acid (38.1)
[0296] To a stirred solution of 37.1 (2.78 g, 8.0 mmol) in anhydrous THE (20
ml) under
an argon atmosphere at -78 C was added n-BuLi (5.5 ml, 8.8 mmol using 1.6 M
solution in
hexane) over a 30 min period. Stirring was continued at -78 C for 15 min, and
then trimethyl
borate (2.7 ml, 24 mmol) was added. Following addition, the reaction mixture
was allowed
to warm to RT over a 12 hour period. The pH was adjusted to 6.5 by addition of
5% aqueous
HC1 solution at 0 C, and the mixture was extracted with dichloromethane. The
organic layer
was washed with brine, dried (MgSO4), and the solvent was evaporated under
reduced
pressure. The residue was purified by flash column chromatography on silica
gel (12%
acetone in hexane) to give 38.1 as colorless oil, in 83% yield (2.1 g).
[0297] 38.1 was confirmed as follows: 'H NMR (500 MHz, CDC13) 8 6.54 (s, 2H),
3.89
(s, 6H), 1.55 (m, 2H), 1.26 (s, 6H), 1.19-1.23 (m, 6H), 1.05 (m, 2H), 0.85 (t,
J = 6.8 Hz, 3H).
Boronic acids 38.2, 38.3, and 38.4
[0298] To a solution of the resorcinol dimethyl ether (37.2 or 37.3 or 37.4, 1
equiv.) in
dry THF, under an argon atmosphere at -78 C was added n-BuLi dropwise (1.1
equiv. using a
1.6 solution in hexanes). The mixture was stirred for 1-6 hours at -78 C, and
then it was
warmed to -10 C and stirred for an additional 1.5 hour. The reaction mixture
was cooled to -
78 C and (MeO)3B (5 equiv.) was added. Following the addition, the mixture was
warmed to
RT and stirred overnight. The reaction was quenched by the dropwise addition
of water, the
pH was adjusted to 4 using a 5% aqueous HCl solution, and the mixture was
extracted with
AcOEt. The organic layer was washed with brine, dried (MgSO4), and the solvent
was
evaporated under reduced pressure. The residue was purified by flash column
chromatography on silica gel (acetone in hexane) to give boronic acid
derivative (38.2 or 38.3
or 38.4) in 75-85% yields.
Selected data of synthesized boronic acids 38.2, 38.3, and 38.4
4-Pentyl-2,6-dimethoxyphenyl boronic acid (38.2)
[0299] 38.2 was confirmed as follows: 'H NMR (500 MHz, CDC13) 6 7.18 (s, 2H),
6.45
(s, 2H), 3.90 (s, 6H), 2.61(t, J = 8.3 Hz, 2H), 1.63 (qt, J = 6.9 Hz, 2H),
1.41-1.29 (m, 4H),
0.91 (t, J = 7.2 Hz, 3H).
3-Hexyl-2,6-dimethoxyphenyl-boronic acid (38.3)
[0300] 38.3 was confirmed as follows: 'H NMR (500 MHz, CDC13) 8 7.28 (d, J =
8.1 Hz,
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1H), 6.72 (d, J = 8.1 Hz, 1H), 3.89 (s, 3H), 3.78 (s, 3H), 2.57 (1n as t, J =
8.5 Hz, 2H), 1.62-
1.56 (m, 2H), 1.37-1.29 (m, 6H), 0.89 (t, J = 7.5 Hz, 3H)
Trifluoromethyl ketones (39)
[0301] A degassed mixture of boronic acid (38) (1.1 equiv.) 4'-bromo-2,2,2-
trifluoroacetophenone (1.0 equiv.), Ba(OH)2'8H2,O (1.5 equiv.) Pd(PPh3)4 (0.03
equiv.), 1,2-
dimethoxyethane and H2O was heated for 4-6 min at 115 C under microwave
irradiation (300
W) using a CEM Discover system. The reaction mixture was cooled to RT, diluted
with
ethyl acetate, and filtered through a short pad of silica gel. The filtrate
diluted with brine and
extracted with ethyl acetate. The organic layer was dried over MgSO4, the
solvent was
evaporated, and the residue was purified by flash column chromatography on
silica gel
(acetone-hexane) to give 39 in 63-78% yields.
Selected data of synthesized trifluoromethyl ketones (39)
1-(2',6'-Dimethoxy-4'-pentylbiphenyl-4-yl)-2,2,2-trifluoroethanone (39.2)
[0302] 39.2 was confirmed as follows: 'H NMR (500 MHz, CDC13) 6 8.13 (d, J =
S.1 Hz,
2H), 7.47 (d, J = 8.1 Hz, 2H), 6.49 (s, 2H), 3.74 (s, 6H), 2.64 (t, J = 7.8
Hz, 2H), 1.72-1.64
(m,2H), 1.43-1.35 (m,4H), 0.93 (t, J = 7.5 Hz, 3H).
1-(2',6'-Dimethoxy-3'-hexylbiphenyl-4-yl) 2,2,2-trifluoroethanone (39.3)
[0303] 39.3 was confirmed as follows: 'H NMR (500 MHz, CDC13) 6 8.16 (d, J =
8.5 Hz,
2H), 7.56 (d, 8.5 Hz, 2H), 7.17 (d, J = 8.3 Hz, 1H), 6.73 (d, J = 8.3 Hz, 1H),
3.73 (s, 3H),
3.27 (s, 3H), 2.61 (t, J = 7.3 Hz, 2H), 1.61 (qt, J = 6.8 Hz, 2H), 1.42 - 1.29
(m, 6H), 0.89 (t, J
= 7.1 Hz, 3H).
1-(2',6'-dihydroxy-4'-(2-methyloctan-2-yl)biphenyl-4-yl)-2,2,2-
trifluoroethanone
(40.1)
[0304] To a solution of 39.1 (500 mg, 1.145 mmol) in dry dichloromethane at 0
C under
an argon atmosphere was added boron tribromide (2.8 mL, using 1 M solution in
CH2Cl,).
Following the addition, the mixture was stirred until the reaction was
completed (4 hours).
Unreacted boron tribromide was destroyed by dropwise addition of water at 0 C.
The
resulting mixture was warmed to RT and diluted with dichloromethane. The
organic layer
was washed with saturated sodium bicarbonate solution, brine, dried over
MgSO4, and
evaporated. Purification by flash column chromatography (18% acetone in
hexane) gave the
title compound in 68% yield (0.318 mg).
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[0305] 40.1 was confirmed as follows: 'H NMR (500 MHz, CDC13) 6 8.21 (d, J =
8.3 Hz,
2H), 7.68 (d, J = 8.3 Hz, 2H), 6.54 (s, 2H), 4.77 (s, 2H, OH), 1.60-1.55 (in,
2H), 1.28 (s, 6H),
1.27-1.19 (in, 6H), 1.16-1.08 (m, 2H), 0.86 (t, J = 6.5 Hz, 3H).
2,2,2-Trifluoro-1-(3'-hexyl-6'-hydroxy-2'-methoxybiphenyl-4-yl)ethanone (40.3)
[0306] Compound 39.3 (1 equiv.) and n-Bu4NI (3 equiv.) were stirred in dry
CH2Cl2 at -
78 C under nitrogen. A solution of BC13 (3.2 mL, using 1 M solution in CH2C12)
was added
over a 2 min period. After 5 min, the solution was warmed to 0 C, and stirring
was continued
for 2 hours. The reaction was quenched with ice-water, the resulting mixture
was stirred for
30 min, and partially concentrated to remove CH2C12. Water was added, and the
mixture was
extracted with diethyl ether. The combined organic layer was washed with
saturated aqueous
NaCl solution, dried over MgSO4, and evaporated. Purification by flash column
chromatography on silica gel (18% acetone in hexane) gave the product (40.3)
in 68% yield
(270 mg).
[0307] 40.3 was confirmed as follows: 'H NMR (500 MHz, CDC13) 8 8.21 (d, J =
8.0 Hz,
2H), 7.52 (d, J = 8.0 Hz, 2H), 7.02 (d, J = 8.3 Hz, 1 H), 6.51 (d, J = 8.3 Hz,
1 H), 4.76 (s, 1 H),
3.96 (s, 3H), 2.57 (t, J = 7.8 Hz, 2H), 1.60 (qt, J = 7.9 Hz, 2H), 1.42-1.28
(1n, 6H), 0.89 (t, J =
7.2 Hz, 3H).
Synthesis of carbamates (46.1-46.3)
[0308] The carbamates 46.1, 46.2 or 46.3 were synthesized by a method depicted
in
Scheme 9 starting from commercially available 4-(4-methoxyphenyl)butanol (41).
Scheme 9
OH / OH / OTBS
a 0 I b ' I C
Me0 HO TBSO
41 42 43
H H
OH / O N-R / O\/N-R
TBSO \ TBSO \ O HO \ O
44 45 46
45.1:R= 46.1:R=
45.2: R= ~_ ) 46.2: R= ~_ )
45.3: R = 46.5: R =
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[0309] Reagents and conditions for the steps in Scheme 9 were as follows: Step
a: BBr3,
CH2CI2, -10 C to RT, 42%; Step b: TBSCI, DMF, RT, 80%; Step c: Sc(OTf)3,
MeCN/H2O,
RT, 73%; Step d: (1) carbonyldiimidazole, CH2C12, 0 C, (ii) RNH,, RT, 46-53%;
Step e:
TBAF, THF, -10 C to RT, 75-82%.
4-(4-Hydroxyphenyl)butanol (42)
[0310] To a stirred solution of 4-(4-methoxyphenyl)butanol (1 equiv.) in dry
dichloromethane at -10 C under an argon atmosphere was added boron tribromide
(2.7
equiv., using a 1 M solution of boron tribromide in CH2CI2). Stirring was
continued at that
temperature until completion of the reaction (4 hours). Unreacted boron
tribromide was
destroyed by addition of aqueous saturated NaHCO3 solution at 0 C. The
resulting mixture
diluted with CH2Ch and water, the organic phase was separated, washed with
brine, dried
(MgS04), and evaporated. Purification by flash column chromatography on silica
gel (30%
diethyl ether-hexane) afforded the title compound in 42% yield.
1-(tert-Butyldimethylsilyloxy)-4-(tert-butyldimethylsilyloxybutyl)-benzene
(43)
[0311] To a solution of imidazole (4 equiv.) in DMF was added 4-(4-
hydroxyphenyl)butanol (1 equiv.) in DMF followed by tent-butyldimethylsilyl
chloride (3
equiv.) in DMF. The reaction was allowed to stir at RT for 15 hours and then
quenched by
addition of saturated aqueous NaHCO3 solution. The resulting mixture was
extracted with
diethyl ether, the ethereal extract was washed with water and brine, and dried
over MgSO4.
Solvent evaporation and purification by flash column chromatography on silica
gel (3%
diethyl ether-hexane) afforded the title compound in 80% yield.
4-(4-tert-Butyldimethylsilyloxy)butanol (44)
[0312] To a solution of 1-(ter=t-butyldimethylsilyloxy)-4-(tert-
butyldimethylsilyloxybutyl)-benzene (Iequiv.) in a mixture of
acetonitrile/water (1:2.5) at RT
was added scandium triflate (0.05 equiv.). The reaction mixture was stirred
for 1 hour,
diluted by addition of CH-,Ch and the organic phase was separated. The aqueous
phase was
extracted with CH2Ch and the combined organic layer washed with brine, dried
(MgSO4),
and evaporated. Purification by flash column chromatography on silica gel (20%
diethyl
ether-hexane) gave the title compound in 73% yield.
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Intermediate carbamates (45)
[0313] To a suspension of carbonyldiimidazole (1.5 equiv.) in anhydrous
dichloromethane at 0 C was added 4-(4-terrt-butyldimethylsilyloxy)butanol (1
equiv.) in
dichloromethane. The reaction mixture was stirred at RT for 1 hour, and then
the appropriate
amine (1.1 equiv.) was added. Stirring was continued until completion of the
reaction (8-10
hours). The reaction mixture was diluted with diethyl ether and 10% aqueous
HCl solution.
The organic phase was separated, washed with brine, dried (MgSO4), and
evaporated.
Purification by flash column chromatography on silica gel (10% diethyl ether-
hexane) gave
intermediate carbamate (45) in 46-53% yield.
Carbamates (46)
[0314] To a stirred solution of intermediate carbamate (45) (1 equiv.) in THE
at -10 C
was added dropwise tetra-n-butyl ammonium fluoride hydrate (1.3 equiv.) in THE
The
reaction mixture was allowed to warm to RT, stirred for 1 hour and diluted
with diethyl ether.
The organic phase was separated, washed with water and brine, dried (MgSO4),
and
evaporated. Purification by flash column chromatography on silica gel gave
carbamate (46)
in 75-82% yield.
Selected data of synthesized carbamates (46)
4-(4-Hydroxyphenyl)butanol isopropylcarbamate (46.1)
[0315] 46.1 was confinned as follows: 1H NMR (400 MHz, CDC13) 8 7.01 (d, J =
8.4 Hz,
2H), 6.76 (d, J = 8.4 Hz, 2H), 4.55 (br s, 1H), 4.06 (t as br s, 2H), 3.81 (m,
1H), 2.54 (t, J =
5.8 Hz, 2H), 1.71-1.59 (m, 4H), 1.14 (d, J = 6.5 Hz, 6H).
4-(4-H droxyphenyl)butanol cyclohexylcarbamate (46.2)
[0316] 46.2 was confinned as follows: 1H NMR (400 MHz, CDC13) 8 6.99 (d, J =
8.3 Hz,
2H), 6.75 (d, J = 8.3 Hz, 2H), 6.23 (br s, 1H), 4.51 (br s, 1H), 4.05 (t as br
s, 2H), 3.48 (in,
1H), 2.55 (t, J = 5.8 Hz, 2H), 1.97-1.85 (m, 2H), 1.75-1.05 (m, 12H).
Synthesis of Carbamates 48.1-6, 52.1-4 and 53.1-4
[0317] The carbamates (48.1-6, 52.1-4 and 53.1-4) were synthesized by a method
depicted in Scheme 10 using commercially available 4-bromoaniline (47.1), 4-
iodoaniline
(47.2), cyclohexanole, 1-adamantanol, 2,6-difluorophenol, phenol, benzyl
chloroformate,
ethyl chloroformate, triphosgene, and the resorcinol derivative (49).
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Scheme 10
H
H2N \ R i 0y N \
a or b O ,
47 X 48 X
47.1: X = Br
47.2: X = I 48.1: R1= ~-O X = Br 48.4: R1= X=Br
48.2: R1= X =Br F
48.3:R1= X=Br
48.5:R1= X Br
F
48.6: R1= Ph,XI
OH OCH20CH3 OCH20CH3
o d (HO)2B
HO CH3OCH2O CH30CH2O
49 50 51
H OCH20CH3
R "O N\I~\ (HO)2B e
1 I I
0 X CH3OCH2O
48 51
48.1: R1 =--( X = Br 48.2: R1 = , X = Br
48.3: R1= X=Br
48.4 : R1= ,X=Br
H H
Rj-' 0 y N OCH20CH3 Ri" 0 y N / I OH
O \ I\ f 0 \ I\
CH3OCH2O HO
52 53
52.1: R1 = ~---( ) 53.1: R1 = --( )
52.2: R1=~/ 53.2: R1=~/
52.3: R1= 53.3: R1=
52.4: R1= 53.4: R1=
[0318] Reagents and conditions for the steps in Scheme 10 were as follows:
Step a:
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BnOCOC1 or EtOCOCI, Na2CO3, toluene, RT, 4-6 hours, 88- 92%; Step b: (i)
(C13CO)2CO,
toluene, reflux, 4-6 hours, (ii) RIOH, RT, 5 hours, 70-78 %; Step c:
CH3OCH7C1, DIPEA,
CH2C12, 0 C to RT, 4 hours, 75 %; Step d: (i) n-BuLl, -10 C, 1.5 hours, (ii)
B(OMe)3, -78 C
to RT, overnight then aqueous HCI, 81 %; Step e: Pd(PPh3)4, Ba(OH)2'8H2O,
DME/H2O,
microwave, 110 C, 4-6 min, 58-77%; Step f: 5N HCI, THE/i-PrOH, RT, 12-18
hours, 60-
72%.
Intermediate carbamates 48.2, and 48.3
103191 To a stirred suspension of4-bromoaniline (47.1) (1 equiv.) and sodium
carbonate
(1.5 equiv.) in anhydrous toluene at RT was added ethyl or benzyl
chloroformate. Stirring
was continued for 4-6 hours at the same temperature. Insoluble materials were
filtered off,
and the filtrate was washed, with water and dried over MgSO4. Solvent
evaporation under
reduced pressure and purification by flash column chromatography on silica gel
(diethyl
ether-hexane) gave pure products (48.2 or 48.3 respectively) in 88-92% yields.
Intermediate carbamates 48.1, 48.4, 48.5, and 48.6
103201 To a stirred suspension of aryl amine (47.1 or 47.2) (1 equiv.) and
sodium
carbonate (1.5 equiv.) in anhydrous toluene, at RT under argon atmosphere was
added
triphosgene (1.2 equiv.). The reaction mixture was heated under reflux until
TLC analysis
indicated the total consumption of starting material (4-6 hours). The reaction
mixture was
cooled to RT, filtered, and the appropriate alcohol (1.1 equiv.) was added to
the filtrate. The
resulting mixture was stirred at RT for 5 hours and the solvent was evaporated
under reduced
pressure. Purification by flash column chromatography on silica gel gave the
pure product in
70-78% yield.
General Procedure for carbamates 48.7-48.9, 53.3-53.8, 53.11, 53.12-53.15,
53.18 and
53.26
[03211 To a stirred solution of substituted aryl amine in 1,2-dimethoxy ethane
(1 equiv.),
was added triphosgene (0.33 equiv.), and the reaction was irradiated with
(Biotage)
microwave, for 8 min at 110 C. The reaction mixture was cooled, an appropriate
alcohol (1
equivalent) was added and again irradiated with microwave for another 10 min
at 120 C. The
reaction mixture was cooled, and ethyl acetate was added. The combined
reaction mixture
was washed with a 5% aqueous sodium bicarbonate solution, and then dried
(MgSO4).
Solvent was evaporated under reduced pressure. Purification by flash column
chromatography on silica gel gave the pure product in 65-85% yield.
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General Procedure for 1-chloroethyl carbonates 46.3, 53.38, and 53.44
[0322] 1-chloroethyl carbonochloridate (0.55 mol) and the indicated alcohol
(0.5 mol)
0
were dissolved in dichloromethane (60 ml) and cooled to 0 C Pyridine (0.055
mol) is then
added dropwise while maintaining the temperature below 15 C. The mixture is
then stirred at
RT until no alcohol remains in solution as indicated by TLC analysis
(generally 4-5 hours).
The resulting mixture is then washed with IN hydrochloric acid (10 ml), then
with a saturated
solution of potassium carbonate (10 ml), and then twice with water (2 X 10
ml). The organic
phase is dried with MgSO4 and solvent is evaporated under reduced pressure.
The resulting
carbonate is purified by flash column chromatography to give pure carbonate in
72-85%
yields.
General procedure for Carbamates 53.21, 53.23, 53.24, 53.39-53.43 and 53.45-
53.47:
[0323] To a solution of the indicated carbonate (1 equiv.) in tetrahydrofuran
(10 ml) is
added to a solution of the amine (1 equiv.) in tetrahydrofuran (30 ml) missed
with a 5 M
solution of potassium carbonate (20 ml) while maintaining temperature at 5-10
C. The
mixture is then stirred at RT until TLC indicates complete consumption of
amine. (1-5 hrs).
The organic phase is separated, washed with a saturated solution of NaCl (20
ml), dried with
MgSO4, and concentrated under reduced pressure. The resulting carbamate is
purified by
column chromatography, to give pure carbamate in 65-82% yield.
Selected data of synthesized intermediate carbamates (48)
(4-Bromophenyl)carbamic acid cyclohexyl ester (48.1)
[0324] 48.1 was confirmed as follows: 1H NMR (500 MHz, CDC13) 6 7.40 (d, J =
8.7 Hz,
2H), 7.28 (br d, J = 8.7 Hz, 2H), 6.58 (br s, 1H, NH), 4.75 (in, 1H), 1.96-
1.89 (in, 2H), 1.78-
1.70 (m, 2H), 1.59-1.52 (m, 1H), 1.50-1.34 (m, 4H), 1.31-1.22 (m, 1H).
(4-Bromophenyl)carbamic acid benzyl ester (48.3)
[0325] 48.3 was confirmed as follows: 'H NMR (500 MHz, CDC13) 6 7.44-7.22 (m,
9H),
6.65 (br s, 1 H, NH), 5.21 (s, 2H)
(4-Iodophenyl)carbamic acid phenyl ester (48.6)
]0326] 48.6 was confirmed as follows: 1H NMR (500 MHz, CDC13) 6 7.63 (d, J =
8.5 Hz,
2H), 7.40 (t, J = 8.5 Hz, 2H), 7.28-7.22 (m, 3H), 7.18 (d, J = 8.0 Hz, 2H),
6.93 (br s, 1H, NH)
1,3-Bis(methoxymethoxy)-5-(1,1-dimethylheptyl)-benzene (50)
[0327] To a stirred solution of resorcinol (49) (1.00 g, 4.23 mmol) and N-
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ethyldiisopropylamine (3.04 mL, 16.92 mmol) in CH2C12 at 0 C was added
chloromethyl
methyl ether (0.82 mL, 10.15 mmol) over 15 min period. The solution was warmed
to RT,
stirred for 4 hours and volatiles were removed in vacuo. The residue was
purified by flash
column chromatography on silica gel (diethyl ether-hexane) to give the title
compound in
75% yield.
2,6-Bis(methoxymethoxy)-4-(1,1-dimethylheptyl)-phenyl boronic acid (51)
[03281 1,3-Bis(methoxymethoxy)-5-(1,1-dimethylheptyl)-benzene (50) (1 equiv.)
was
dissolved in dry THE (10 mL). The solution was cooled to -10 C, and n-BuLi
(1.1 equiv.
using 1.6 solution in hexanes) was added dropwise. The mixture was stirred for
an additional
1.5 hours, and then cooled to -78 C. (MeO)3B (5 equiv.) was then added. The
reaction
mixture was allowed to warm to RT and stirred overnight. The mixture was
diluted with
water, stirred for 30 min and the pH was adjusted to 4 with dilute aqueous
HC1. The mixture
was extracted with EtOAc, the organic layer was dried (MgSO4), and the solvent
was
evaporated. Purification by flash column chromatography (hexane-acetone) gave
the title
compound in 81 % yield.
[03291 51 was confirmed as follows: 'H NMR (500 MHz, CDC13) 6 7.21 (s, 2H),
6.86 (s,
2H), 5.31 (s, 4H), 3.53 (s, 6H), 1.62-1.56 (m, 2H), 1.31-1.18 (m, 12H,
especially 1.29, s, 6H),
1.12-1.04 (m, 2H), 0.87 (t, J = 6.5 Hz, 3H).
Carbamates (52)
[03301 A degassed mixture of boronic acid (51) (1.1 equiv.), 4-bromo-2,2,2-
trifluoroacetophenone (1.0 equiv.), Ba(OH)2'8H2O (1.5 equiv.), Pd(PPh3)4 (0.03
equiv.), 1,2-
dimethoxy ethane and water was heated for 4-6 min at 110 C under microwave
irradiation
using a CEM discover system. The reaction mixture was cooled to RT, diluted
with ethyl
acetate, and filtered through a short pad of silica gel. The filtrate diluted
with brine and
extracted with ethyl acetate. The organic layer was dried over MgSO4, the
solvent was
evaporated, and the residue was purified by flash column chromatography on
silica gel
(acetone-hexane) to give product 52 in 58-77% yields.
Selected data of synthesized carbamates (52)
2',6'-Bis(methoxyinethoxy)-4'-(I, 1-dimethylheptyl)11.1'-biphenyll-4-y1
carbamic acid ethyl ester (52.2)
[0331] 52.2 was confirmed as follows: 'H NMR (500 MHz, CDC13) 6 7.40 (br d, J
= 8.9
Hz, 2H), 7.34 (d, J = 8.9 Hz, 2H), 6.86 (s, 2H), 6.58 (br s, 1H, NH), 5.00 (s,
4H), 4.24 (q, J =
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7.5 Hz, 2H), 3.31 (s, 6H), 1.61-1.57 (m, 2H), 1.32 (t, J = 7.5 Hz, 3H), 1.29
(s, 6H), 1.27-1.20
(m, 6H), 1.17-1.10 (m, 2H), 0.86 (t, J = 7.6 Hz, 3H)
2'.6'-Bis(methoxymethoxy)-4'-(1,1-dimethVlheptyl)[ 1.1'-biphenyl]-4-y1
carbamic acid benzyl ester (52.3)
[0332] 52.3 was confirmed as follows: 'H NMR (500 MHz, CDC13) 8 7.43-7.33 (m,
9H),
6.86 (s, 2H), 6.68 (br s NH), 5.22 (s,2H), 5.00 (s, 2H), 3.30 (s, 6H), 1.60-
1.57 (m, 2H), 1.29
(s, 2H), 1.28-1.22 (m, 6H), 1.17-1.10 (m, 2H), 0.86 (t, J = 7.0 Hz, 3H)
2. Carbamates (53)
[0333] To a stirred solution of 52 (1.0 equiv.) in isopropyl alcohol/THF
mixture (1:1)
were added few drops of 5N HCl solution. This mixture was stirred overnight at
RT and
evaporated to dryness. The residue was purified by flash column chromatography
on silica
gel (acetone-hexane) to give the product 53 in 60-72% yields.
3. Selected data of synthesized carbamates (53)
2',6'-Dih day-4'-(2-methyloctan-2-ylphenyl-4-yl carbamic acid
cyclohexyl ester (53.1)
[0334] 53.1 was confirmed as follows: 'H NMR (500 MHz, CDC13) 6 7.59 (br d, J
= 8.3
Hz, 2H), 7.38 (d, J = 8.3 Hz, 2H), 6.66 (br s, IH, NH), 6.56 (s, 2H), 4.82-
4.74 (m and s,
overlapping, 3H, especially 4.76, s, 2H, OH), 1.99-1.93 (m, 2H), 1.79-1.74 (m,
2H), 1.61-
1.54 (m, 2H), 1.52-1.37 (m, 6H), 1.33-1.18 (m and s, overlapping, 12 H,
especially 1.27, s,
6H, -C(CH3)2), 1.17-1.08 (m, 2H), 0.86 (t, J = 7.0 Hz, 3H)
2'.6'-Dihydroxy-4'-(1,1-dimethylheptyl)11,1'-biphenyl]-4-y1 carbarnic acid
ethyl ester (53.2)
[0335] 53.2 was confirmed as follows: 'H NMR (500 MHz, CDC13) 8 7.58 (br d, J
= 8.3
Hz, 2H), 7.38 (d, J = 8.3 Hz, 2H), 6.68 (br s, 1H, NH), 6.56 (s, 2H), 4.74 (s,
21-1, OH), 4.27 (q,
J = 7.5 Hz, 2H), 1.59-1.54 (rn, 2H), 1.34 (t, J = 7.5 Hz, 3H), 1.27 (s, 6H),
1.24-1.19 (m, 6H),
1.15-1.08 (m, 2H), 0.86 (t, J = 7.2 Hz, 3H).
2',6'-Dih day-4'-(2-methyloctan-2-yl)biphenyl-4-yl carbamic acid benzyl
ester (53.3)
[0336] 53.3 was confirmed as follows: 'H NMR (500 MHz, CDC13) 8 7.59 (d, J =
8.0 Hz,
2H), 7.44-7.36 (m, 7H), 6.77 (br s, 1H, NH), 6.56 (s, 2H), 5.23 (s, 2H), 4.73
(s, 2H), 1.58-
1.55 (m, 2H), 1.28-1.18 (m and s, overlapping, 12 H. especially 1.26, s, 6H, -
C(CH3)2), 1.15-
1.09 (m, 2H), 0.86 (t, J = 7.0 Hz, 3H).
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Synthesis of Carbamates 57.1 and 57.2
[0337] The carbamates 57.1 and 57.2 were synthesized by a method depicted in
Scheme
11 starting from commercially available 4-bromobenzyl bromide (54).
1. Scheme 11
Br I a N3 I b H2N i c
Br Br Br
54 55 56
OII
R1,,OJ~ H
Br
57
57.1: R1 = Et
57.2: R, = CH2Ph
[03381 Reagents and conditions for the steps in Scheme 11 were as follows:
Step a:
NaN3, DMF, 50 C, 3 hours, 92%; Step b: PPh3, THE/CH30H, reflux, 1.5 hours,
63%; Step c:
RIOCOCI, Na2CO3, toluene, RT, 4-6 hours, 82-90 %.
2. 4-Bromobenzyl azide (55)
[0339] A mixture of 4-bromobenzyl bromide (54) and sodium azide (2.0 equiv.)
in DMF
was stirred at 50 C for 3 hours. The reaction mixture was diluted with water
and extracted
with CH2C12. The combined organic extract was dried over M,-,S04, and
concentrated in
vacuo. The residue was purified by flash chromatography to yield 55 as
colorless oil in 92%
yield.
[0340] 55 was confirmed as follows: 'H NMR (500 MHz, CDC13) 8 7.51 (d, J = 8.5
Hz,
2H), 7.19 (d, J = 8.5 Hz, 2H), 4.31 (s, 2H). IR (Neat): 2091, 1592, 1488 cm I.
3. 4-Bromobenzyl amine (56)
[03411 To a stirred solution of azide 55 (0.75 g, 3.54 mmol) in anhydrous
methanol
(10 mL) was added triphenylphosphine (1.39 g, 5.31 mmol) and the mixture was
heated
under reflux for 1.5 hours. The reaction mixture was cooled to RT, and the
solvent was
removed under reduced pressure. The residue was purified by flash column
chromatography
on silica gel (acetone-hexane) to yield product 56 in 63% yield (0.41 g).
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4. Carbamates (57)
[0342] To a stirred suspension of 4-bromobenzyl amine 56 (1 equiv.) and sodium
carbonate (1.5 equiv.) in anhydrous toluene at RT was added ethyl or benzyl
chloroformate.
Stirring was continued for 4-6 hours at the same temperature, insoluble
materials were
filtered off, and the filtrate was washed with water and dried over MgSO4.
Solvent
evaporation under reduced pressure and purification by flash column
chromatography on
silica gel (diethyl ether-hexane) gave pure product (57.1 or 57.2
respectively) in 82-90%
yields.
5. Selected data of synthesized carbamates (57)
(4-Bromobenzyl)carbamic acid benzyl ester (57.2)
[0343] 57.2 was confirmed as follows: 'H NMR (500 MHz, CDC13) 8 7.44 (d, J =
7.7 Hz,
2H), 7.38-7.30 (m, 5H), 7.16 (d, J = 7.7 Hz, 2H), 5,13 (s, 2H), 5.09 (br s,
1H, NH), 4.32 (d, J
= 5.5 Hz, 2H).
Carbamates 57.3, 57.4, and 57.5
[0344] The carbamates 57.3, 57.4 and 57.5 were synthesized by a method
depicted in
Scheme 12.
Scheele 12
cocI Ph N O
O O
57a 57.3
OH b R I O\ /CI c Ph N~O
~[ c
R, , ~ 0 0
R,
57b 57c
57b.1 R 3 NMe 57c.1 R1 = 3-NMe2 57.4: Ri = 3-NMe2
2 57c.2 R, = 3-CN 57.5: R, = 3-CN
57b.2 R1 = 3-CN
[0345] Reagents and conditions for the steps in Scheme 12 were as follows:
Step a:
4-phenylpiperidine, CH202, RT, 12 hours; Step b: (i) NaH, THF, 0 C - RT, 1
hour (ii)
triphosgene, RT, 1 hour; Step c: 4-phenylpiperazine, RT, 12 hours.
1. Carbamates (57.3)
[0346] To a stirred solution of 4-phenyl piperazine (2.2 equiv.) in an ydrous
CH2C12 at
RT was added phenylchoroformate 57a (1.0 equiv.) and the resulting mixture
stirred at the
same temperature (12 hours). The mixture was washed with 5% HCl (aq.), the
organic layer
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was washed with brine and dried over MgSO4. Solvent evaporation under reduced
pressure
gave pure product (57.3 in 96% yield).
[0347] 57.3 was confirmed as follows: 'H NMR (500 MHz, CDC13) 6 7.41-7.35 (m,
4H),
7.27-7.25 (m, 3H), 7.23 (t, J = 7.5 Hz, 1H), 7.15 (d, J = 7.7 Hz, 2H), 4.47
(t, J = 15 Hz, 2H),
3.12(t,J=11.5Hz,IH),2.97(t,J=12.0Hz,1H),2.77(tt,J=12.5 Hz, J= 3.5 Hz,J=3.5
Hz), 1.96 (d, J = 13 Hz, 2H), 1.79 (dq, J = 12.0 Hz, J = 4.5 Hz).
2. Carbamates (57.4 and 57.5)
[0348] To a stirred solution of phenols 57b.2 or 57b.2 (1.0 equiv.) in THE at
0 C was
added NaH (60% dispersion in mineral oil, 1.05 equiv.) and the resulting
mixture gradually
warmed to RT. Triphosgene (0.33 equiv.) was added, and the mixture stirred for
additional 2
hours at the same temperature. This mixture (1.0 equiv,) was added to a
solution of 4-
phenylpiperazine (2.2 equiv.) in CH2C12, and the mixture stirred for 12 hours.
The mixture
was washed with 1 N NaOH (aq.), the organic layer was washed with brine, and
then dried
over MgSO4. Solvent evaporation under reduced pressure gave a crude product,
which was
purified by column chromatography on silica ge (25% EtOAc:Hexane) to give
(57.4 and 57.5
in 45-48% yield (from 57b.1 or 57b.2).
3. Compound 57.4
[0349] 57.4 was confirmed as follows: 'H NMR (500 MHz, CDC13) 6 7.38-7.34 (m,
2H),
7.26 (t, J = 7.0 Hz, 2H), 7.22 (t, J = 8.5 Hz, I H), 7.10 (t, J = 8.5 Hz, I
H), 6.58(dd, J = 7.7 Hz,
J = 2.5 Hz, 1 H), 6.52-6.48 (m, 2H), 4.47 (t, J = 15.0 Hz, 2H), 3.10 (m, 1 H),
2.97 (m
overlapping with singlet 4H), 2.95 (s, 3H), 2.77 (tt, J = 12.5 Hz, J = 3.5 Hz,
J = 3.5 Hz), 1.96
(d, J = 13 Hz, 2H), 1.79 (dq, J = 12.0 Hz, J = 4.5 Hz).
4. Compound 57.5
[0350] 57.5 was confirmed as follows: 1H NMR (500 MHz, CDC13) 6 7.51-7.46 (in,
3H),
7.44-7.40 (m, 1H), 7.36-7.32 (in, 2H), 7.26-7.22 (m, 3H), 4.41 (t, J = 14.0
Hz, 2H), 3.12 (t, J
=12.2Hz,1H),2.98(t,J=13.0Hz,1H),2.76(tt,J=12.5Hz, J= 4.0 Hz, J = 4.0 Hz), 1.96
(d, J= 14.0 Hz, 2H), 1.79(dd,J=13.0Hz,3=4.0Hz).
Synthesis of Ureas 59.1 and 59.2
[0351] Ureas 59.1 and 59.2 were synthesized by a method depicted in Scheme 13
starting from commercially available 3-phenyl-propyl isocyanate (58) and 2-
aminomethyl-
pyridine or 2-aminopyridine.
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1. Scheme 13
H H
a NuN,R
0- (CH2)3-N=C=O III
O
58 59
N
59.1 R=
59.2: R = iN
[0352] Reagents and conditions for Scheme 13 were as follows: Step a: R-NH2,
THE or
benzene, 0 C to reflux 85-93%.
2. N-('3 -phenylpropyl)-N'-(2-p i lmethyl)-urea (59.1)
[0353] To a solution of 3-phenylpropyl isocyanate (1.8 mmol) in anhydrous THE
(10
mL) at 0 C under an argon atmosphere was added 2-aminomethyl-pyridine (1.8
mmol). The
reaction mixture was stirred at 0 C for 10 min, the solvent was evaporated
under reduced
pressure, and the resultant solid was recrystallized from CH?C12/Et,,O to give
pure 59.1 in
92% yield (white solid, melting point 89-90 C). When anhydrous benzene was
used as
solvent the product was directly crystallized out and isolated by filtration
(93% yield).
[0354] 59.1 was confirmed as follows: 'H NMR (500 MHz, CDC13) d 8.47 (d, J =
4.4 Hz,
1H), 7.61(td, J = 7.6 Hz, J = 1.1 Hz, 1H), 7.28-7.22 (in, 3H), 7.19-7.10 (m,
4H), 5.97 (t, J =
4.9 Hz, IH, NH), 5.30 (br s, 1H, NH), 4.45 (d, J = 5.4 Hz, 2H), 3.20 (td as q,
J = 6.4 Hz, 2H),
2.61 (t, J = 7.6 Hz, 2H), 1.79 (quintet, J = 7.3 Hz, 2H); IR (neat), 3320,
3028, 2941, 2860,
1620, 1594, 1568, cm-1.
3. N-(3 -phenylpropyl)-N'-(2-p r yl)-urea (59.2)
[0355] To a stirred solution of 3-phenylpropyl isocyanate (2 mmol) in
anhydrous THE
(15 mL) at 0 C under an argon atmosphere was added 2-amino-pyridine (2 mmol).
Following
the addition, the reaction mixture was heated under reflux for 2 hours, the
solvent was
evaporated under reduced pressure, and the resultant solid was recrystallized
from
CH2CI2/Et2O to give pure 59.2 in 85% yield (white solid, melting point 127-128
C).
[0356] 59.2 was confirmed as follows: 'H NMR (500 MHz, CDC13) 8 9.72 and 9.66
(s
and br s, overlapping, 2H, NH), 8.16 (d, J = 4.3 Hz, I H), 7.58 (t, J = 7.1
Hz, I H), 7.30 (t, J =
7.4 Hz, 2H), 7.24 (d, J = 7.4 Hz, 2H), 7.21 (t, J = 7.4 Hz, 1H), 6.94 (d, J =
7.1 Hz, 1H), 6.87
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(in as t, J = 6.4 Hz, 1 H), 3.44 (td as q, J = 6.4 Hz, 2H), 2.75 (t, J = 7.6
Hz, 2H), 1.97 (quintet,
J = 7.2 Hz, 2H); IR (neat) 3221, 3054, 2980, 2918, 1682, 1602, 1583, 1549,
1480 cm-1
.
Synthesis of Ureas 59.3 - 59.7
[0357] Ureas 59.3 though 59.7 were synthesized by a method depicted in Scheme
14.
1. Scheme 14
a 0
NCO R1 '
R1~ _ / H H~Ph
58a 59.3 R, = 4-OMe
58a.1 R1 = 4-OMe 59.4 R1 = H
58a.2 R1 = H
NCO 0
R \ b R1
HN~X_y
58a.2 R1 = H
58a.3 R CN 59.5 R1 = H, X = CH, Y = Ph
1 59.6 R1 = 4-CN, X = CH, Y = Ph
59.7 R, = 4-CN, X = N, Y = CH2Ph
[0358] Reagents and conditions for the steps in Scheme 14 were as follows:
Step a: 4-phenyl-cyclohexylamine, CH2C12, RT, 2 hours;
Step b: 4-phenylpiperidine or 4-benzylpiperazine, CH2C12, RT, 2 hours.
2. N-(4-methoxyphenyl)-N'-(4-phenylc cl~ ohexyl-urea (59.3)
[0359] To a stirred solution of 4-methoxyphenyl isocyanate 58a.1 (1 equiv)) in
CH2C12 at
RT under an argon atmosphere was added 4-phenyl-cyclohexyl amine (2.2 equiv.)
and the
resulting mixture stirred for 2 hours. The mixture was washed with 5% HCI
(aq.), the
organic layer was dried over MgS04, and the solvent removed under reduced
pressure. The
crude material was purified by flash column chromatography on silica gel to
give 59.3 in
77% yield.
[0360] 59.3 was confirmed as follows: IH NMR (500 MHz, CD3OD) 6 7.36 (dd, J =
8.5
Hz, J = 1.0 Hz, 2 H), 7.30-7.23 (m, 6H), 7.16 (t, J = 7.0 Hz, 1H), 6.98 (t, J
= 7.01 Hz, 1H),
3.64(tt,J= 12.0 Hz, J = 4.5 Hz, J = 4.0 Hz, 1H),2.54(tt,J=11.8Hz,J=3.5Hz,J=3.5
Hz), 2.10 (d, J = 13.5 Hz, 2H), 1.94 (d, J = 13.5 Hz, 2H), 1.65 (dq, J = 12.5
Hz, J = 3.5 Hz,
2H), 1.39 (dd, J = 12.5 Hz, J = 3.5 Hz, 2H).
3. N-(phenyl)-N'-(4-phenylcyclohexy)-urea (59.4)
[0361] 59.4 was confirmed as follows: 1H NMR (500 MHz, CD3OD) 6 7.29-7.22 (m,
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7H), 7.16 (t, J = 7.0 Hz, 1H),6.85(d,J=8.5Hz,2H),3.64(tt,J=12.0Hz,J=4.0Hz,J=
4.0 Hz, 1H),2.53 (tt, J = 12.0 Hz, J = 3.5 Hz, J = 3.5 Hz), 2.11 (d, J= 8.5
Hz, 2H), 1.93 (d,J
= 9.0 Hz, 2H), 1.64 (dq, J = 13.0 Hz, J = 3.0 Hz, 2H), 1.38 (dq, J = 12.5 Hz,
J = 3.5 Hz, 2H).
4. N-(phenyl)-(4-phenylpiperidine)-1-carboxamide (59.5)
[03621 To a stirred solution of phenyl isocyanate 58a.2 (1 equiv)) in CH2C12
at RT under
an argon atmosphere was added 4-phenyl-piperidine (2.2 equiv.) and the
resulting mixture
stirred for 2 hours. The mixture was washed with 5% HCl (aq.), the organic
layer was dried
over MgSO4, and the solvent removed under reduced pressure. The crude material
was
purified by flash column chromatography on silica gel to give 59.5 in 73%
yield.
[03631 59.5 was confirmed as follows: 'H NMR (500 MHz, CDC13) '6 7.41-7.30 (m,
7H),
7.27-7.24 (m, 3H), 6.42 (brs, 1 H), 4.25 (d, J = 13.5 Hz, 2H), 3.04 (dt, J =
12.5 Hz, J = 2.0 Hz,
2H), 2.76 (tt, J = 12 Hz, J = 3.8 Hz, J = 3.8 Hz, IH), 1.96 (d, J = 12.5 Hz,
2H), 1.77 (dq, J =
13.0 Hz, J= 4.5 Hz, 2H).
5. N-(4-cyanophenyl)-(4-phenylpiperidine)-1-carboxamide (59.6)
[03641 N-(4-cyanophenyl)-(4-phenylpiperidine)-1-carboxamide (59.6) was
prepared as
described for 59.5 using 4-cyanophenyl isocyanate 58.a.3 (l equiv.) and 4-
phenyl piperidine
(2.2 equivalent) in CH2CI2 to give 59.6 in 75% yield.
[0365] 59.6 was confirmed as follows: 'H NMR (500 MHz, CDC13) b 7.56 (d, J =
8.5 Hz,
2H), 7.52 (d, J = 9.0 Hz, 2H), 7.33 (t, J = 7.2 Hz, 2H), 7.25-7.20 (m, 3H),
6.76 (brs, 1H),
4.23 (d, J = 13.5 Hz, 2H), 3.05 (dt, J = 13.0 Hz, J = 2.0 Hz, 2H), 2.75 (tt, J
= 12 Hz, J = 3.5
Hz, J = 3.5 Hz, 1 H), 1.95 (d, J = 12.5 Hz, 2H), 1.77 (dq, J = 12.5 Hz, J =
4.0 Hz, 2H).
6. N-(4-cyanophenyl)-(4-beezylpiperidine)--carboxamide (59.7)
[03661 N-(4-cyanophenyl)-(4-benzylpiperidine)--carboxamide (59.7) was prepared
as
described for 59.5 using 4-cyanophenyl isocyanate 58a.3 (1 equiv)) and 4-
benzyl-piperidine
(2.2 equiv.) in CH2C12 to give give 59.7 in 76% yield.
[03671 59.7 was confirmed as follows: 'H NMR (500 MHz, CDC13) b 7.58-7.55 (in,
2H),
7.52-7.50 (m, 2H), 7.38-7.29 (m, 5H), 6.70 (brs, 1H), 3.60 (s, 2H), 3.56-3.54
(m, 4H), 2.54-
5.51 (m, 4H).
Synthesis of a-Keto-oxadiazoles 65.1, 65.2, and 66
[0368] a-Keto-oxadiazoles 65.1, 65.2 and 66 were synthesized by a method
depicted in
Scheme 15 starting from 60.1 or 60.2 and 2-methyl-oxadiazole (63). Phenol
(60.1) and 4-
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benzyloxy-phenol (60.2) were commercially available while 2-methyl-oxadiazole
(63) was
prepared by a method disclosed in Ainsworth et al., J. Org. Chem. Soc., (1966)
31:3442-
3444, and in Ohmoto et al., J. Med. Chem., (2001) 44:1268-1285.
1. Scheme 15
R \ OH a R \ O 0OOEt b R \ O~ CHO
60 61 62
60.1:R=H 61.1:R=H 62.1:R=H
60.2=19.1: R=OBn 61.2=20.4:R=OBn 62.2: R=OBn
OH 0
N-N N, N.
c R\ O,",~i N d R /\ O 5 i .( N
0 O \
63 64 65
64.1: R=H 65.1: R = H
64.2: R = OBn 65.2: R = OBn
0
e ,N
H 66
[0369] Reagents and conditions for the steps in Scheme 15 were as follows:
Step a:
Br(CH7)6COOEt K7C037 18-crown-6, acetone, 50 C, 12 hours, 90-92%; Step b:
DIBAL-H,
THF, -78 C, 1 hour, 63-65%; Step c: n-BuLi, MgBr2'Et7O, THE -78 C to -50 C,
then addition
to 62.1 or 62.2, CeC13, -78 C, 52-55%; Step d: Dess-Martin periodinane,
CH2C12, RT, 80-
82%; Step e: Pd/C, H2, AcOEt, RT, 71%.
2. 7-(Phenoxy)heptanoic acid ethyl ester (61.1)
[03701 To a solution of 60.1 (0.7 g, 7.5 mmol) in dry acetone (50 mL), under a
nitrogen
atmosphere, was added 18-crown-6 (1.584 g, 6 mmol), anhydrous potassium
carbonate (2.07
g, 15 mmol), and ethyl 7-bromoheptanoate (1.18 g, 5 mmol) successively. The
mixture was
stirred at 50 C overnight, cooled to RT, and the solvent removed in vacuo. The
residue
obtained was partitioned between diethyl ether (50 mL), and water (10 mL). The
organic
phase was separated and the aqueous layer extracted with diethyl ether. The
combined
organic layer was washed with brine, dried (MgSO4), and the solvent was
removed under
reduced pressure. Purification by flash column chromatography (20% diethyl
ether-hexane)
afforded 61.1 (1.72 g, 92% yield) as a colorless liquid.
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[03711 61.1 was confirmed as follows: 'H NMR (500 MHz, CDC13) d 7.27 (dt, J =
7.7
Hz,J=1.5Hz,2H),6.92(dt,J=7.7Hz,J=1.5Hz1H),6.89(d, J = 7.7 Hz,2H),4.12(q,J=
7.0 Hz, 2H), 3.95 (t, J = 6.2 Hz, 2H), 2.31 (t, J = 7.7 Hz, 2H), 1.78
(quintet, J = 6.5 Hz, 2H),
1.66 (quintet, J = 7.5 Hz, 2H), 1.49 (quintet, J = 7.2 Hz, 2H), 1.40 (quintet,
J = 8.2, 2H), 1.25
(t, J = 7.0 Hz, 2H).
3. 7-[4-(Benz yloxy)phenoxy]heptanoic acid ethyl ester (61.2/20.4)
[03721 An alternative method for the synthesis of the title compound was
carried out
analogous to the preparation of 61.1 using 60.2 (0.45 g, 2.255 mmol), 18-crown-
6 (1.056 g, 4
mmol), potassium carbonate (1.38 g, 10 mmol), and Br(CH2)6COOEt, (0.8 g, 3.37
mmol) in
dry acetone (40 mL). Purification by flash column chromatography on silica gel
(20%
diethyl ether-hexane) gave 61.2/20.4 (1.08 g, 90% yield) as a white solid
(melting point 57-
61 C).
[03731 61.2/20.4 was confirmed as follows: 'H NMR (500 MHz, CDC13) 6 7.42 (d,
J =
7.5 Hz, 2H), 7.37 (t, J = 7.5 Hz, 2H), 7.31 (t, J = 7.5 Hz, 1H), 6.89 (d, J =
8.7 Hz, 2H), 6.82
(d, J = 8.7 Hz, 2H), 5.01 (s, 2H), 4.12 (q, J = 7.0 Hz, 2H), 3.89 (t, J = 6.5
Hz,2H),2.30(t,J
7.5 Hz, 2H), 1.76 (quintet, J = 6.7 Hz, 2H), 1.66 (quintet, J = 7.5 Hz, 2H),
1.47 (quintet, J =
7.2 Hz, 2H), 1.38 (quintet, J = 6.7 Hz, 2H), 1.25 (t, J = 7.0 Hz, 2H).
4. 7-(Phenoxy)heptanal (62.1)
[0374] To a stirred solution of 61.1 (0.56 g, 2.24 mmol) in dry THE (20 mL),
at -78 C,
under a nitrogen atmosphere was added diisobutylaluminum hydride (5mL, 5mmol,
using a 1
M solution in hexanes) dropwise. The reaction mixture was stirred at the same
temperature
for 30 min and then quenched by dropwise addition of potassium sodium tartrate
(10%
solution in water) . The resulting mixture was warmed to RT and stirred
vigorously for 1
hour. The organic layer was separated and the aqueous phase extracted with
diethyl ether.
The combined organic layer was washed with brine, dried (MgSO4), and
concentrated in
wacuo. The residue was purified by column chromatography on silica gel,
eluting with 25%
diethyl ether-hexane to give 62.1 (0.26 g, 65% yield) as a colorless viscous
liquid.
[0375] 62.1 was confirmed as follows: 'H NMR (500 MHz, CDC13) b 9.80 (s, 1H),
7.27
(t, J = 7.5 Hz, 2H), 6.93 (d, J = 7.5 Hz, 2H), 6.89 (d, J = 7.5 Hz, 2H), 3.95
(t, J = 6.2 Hz, 2H),
2.45 (t, J = 7.2 Hz, 2H), 1.79 (quintet, J = 6.7 Hz, 2H), 1.67 (quintet, J =
7.0 Hz, 2H), 1.50
(quintet, J = 6.7 Hz, 2H), 1.41 (quintet, J = 7.7 Hz, 2H).
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5. 7-14-(Benzyloxy)phenoxylheptanal 62.2
[03761 7-[4-(Benzyloxy)phenoxy]heptanal 62.2 was synthesized analogous to the
preparation of 62.1 using 61.2/20.4 (0.624 g, 2 mmol) and diisobutylaluminum
hydride (4.5
mL, 4.5 mmol, using a 1 M solution in hexanes) in THE (20 mL). Purification by
flash
column chromatography on silica gel gave 62.2 (0.39 g, 63% yield) as a white
solid (melting
point 65-67 C).
[0377] 62.2 was confirmed as follows: 1H NMR (500 MHz, CDC13) b 9.80 (s, 1H),
7.42
(d, J = 7.2 Hz, 2H), 7.38 (t, J = 7.2 Hz, 2H), 7.31 (t, J = 7.2 Hz, 1H), 6.90
(d, J = 8.7 Hz, 2H),
6.82 (d, J = 8.7 Hz, 2H), 5.01 (s, 2H), 3.90 (t, J = 6.2 Hz, 2H), 2.44 (dt, J
= 7.2 Hz, J = 2.0
Hz, 2H), 1.76 (quintet, J = 7.5 Hz, 2H), 1.67 (quintet, J = 7.5 Hz, 2H), 1.48
(quintet, J = 7.2
Hz, 2H), 1.40 (quintet, J = 7.7 Hz, 2H).
6. 7-Phenoxy-l-(5-meth l 1,3,4-oxadiazol-2-yl)-heptan-l-ol (64.1)
[03781 To a stirred solution of 63 (0.252 g, 3 mmol) in anhydrous THE (5 mL),
at -78 C,
under a nitrogen atmosphere, was added n-BuLi (1.2 mL, 3 mmol, using a 2.5 M
solution in
hexanes) dropwise. Stirring was continued for 15 min at -78"C, and then
MgBrz'Et20 (0.774
g, 3 mmol) was added. The resulting mixture was warmed to -50 C over a 2 hour
period, and
then it was transferred by cannula to a cooled (-78 C) slurry of 62.1 (0.125
g, 0.6 mmol) and
CeC13, (0.738 g, 3 mmol) in anhydrous THE (6 mL), which was previously stirred
at RT for 2
hours under nitrogen. Following the addition, the resultant mixture was
allowed to warn to
RT over a 4 hour period. The reaction mixture was quenched with dropwise
addition of 5%
aqueous AcOH solution (10 mL), diluted with AcOEt (20 mL), and the organic
phase was
separated. The aqueous layer extracted with AcOEt, the combined organic layer
was washed
with an aqueous saturated NaHCO3 solution and brine, dried (MgSO4), and the
solvent was
evaporated under reduced pressure. The residue obtained was purified by flash
column
chromatography on silica gel (75% ethyl acetate-hexane) to give 64.1 (92.5
ing, 53% yield)
as a white solid (melting point 50-52C).
[03791 64.1 was confirmed as follows: 'H NMR (500 MHz, CDC13) b 7.27 (t, J =
7.7 Hz,
2H), 6.93 (t, J = 7.7 Hz, I H), 6.89 (d, J = 7.7 Hz, 2H), 4.91 (t, J = 6.2 Hz,
I H), 3.95 (t, J = 6.7
Hz, 2H), 2.80 (br s, 1 H), 2.54 (s, 3H), 1.98-1.90 (m, 2H), 1.78 (quintet, J =
6.7 Hz, 2H), 1.54-
1.40 (in, 6H).
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7, 7- 4-Benzyloxy-phenoxy)-1-(5-methyl-1.3,4-oxadiazol-2-yl)-heptan-l-ol
(64.2)
[0380] The synthesis was carried out analogous to the preparation of 64.1
using 62.2 (0.1
g 0.32 mmol), cerium chloride (0.44 g, 1.6 mmol) and 63 (0.42 g, 1.6 mmol).
Purification
by flash column chromatography on silica gel gave pure 64.2 (0.077 mg, 55%
yield) as a
white solid (melting point 98-100 C).
[0381] 64.2 was confirmed as follows: 'H NMR (500 MHz, CDC13) 8 7.42 (d, J =
7.5 Hz,
2H), 7.38 (t, J = 7.5 Hz. 2H), 7.31 (t, J = 7.5 Hz, I H), 6.90 (d, J = 8.7 Hz,
2H), 6.82 (d, J =
8.7 Hz, 2H), 5.01 (s, 2H), 4.90 (q, J = 6.0 Hz,
1H),3.89(t,J=6.5Hz,2H),2.54(s,3H),2.51
(d, J = 6.0 Hz, I H), 2.00-1.92 (m, 2H), 1.75 (quintet, J = 7.5 Hz, 2H), 1.56-
1.40 (m, 6H).
8. 7-Phenoxy-l-(5-methyl-1.3,4-oxadiazol-2-yl)-heptan-l-one (65.1)
[0382] To a solution of 64.1 (64 mg, 0.22 mmol) in wet methylene chloride (5
ml-) at RT,
under nitrogen was added Dess-Martin periodinane (140 mg, 0.33 mmol) and the
resulting
suspension stirred for 2 hours. The reaction mixture was diluted with Na2S~O3
(10% in HBO)
and saturated aqueous NaHCO3 solution, and the organic phase was separated.
The aqueous
layer was extracted with AcOEt, and the combined organic layer was washed with
brine,
dried (MgSO4), and evaporated under reduced pressure. The residue obtained was
purified
by flash column chromatography on silica gel (50% ethyl acetate-hexane) to
give 65.1 (52
mg, 82% yield) as a white solid (melting point 75-77C).
[0383] 65.1 was confirmed as follows: 1H NMR (500 MHz, CDC13) 8 7.27 (t, J =
7.5 Hz,
2H), 6.93 (t, J = 7.5 Hz, 1 H), 6.89 (d, J = 7.5 Hz, 2H), 3.95 (t, J = 6.2 Hz,
2H), 3.15 (t, J = 7.2
Hz, 2H), 2.64 (s, 3H), 1.84-1.77 (m, 4H), 1.52-1.44 (m, 4H).
9. 7-(4-Benzyloxy-phenoxy)-1-(5-methyl-1,3,4-oxadiazol-2-yl)-heptan-l-one
(65.2)
[0384] The synthesis was carried out analogous to the preparation of 65.1
using 64.2 (60
Ing, 0.15 mmol) and Dess-Martin periodinane (0.127 g, 0.3 mmol) in wet CH-)Ch
(5 mL).
Purification by flash column chromatography on silica gel gave pure compound
65.2 (47.5
mg, 80% yield) as a white solid (melting point 118-120C).
[0385] 65.2 was confirmed as follows: 1H NMR (500 MHz, CDC13) 6 7.42 (d, J =
7.5 Hz,
2H), 7.3 8 (t, J = 7.5 Hz, 2H), 7.31 (t, J = 7.5 Hz, 1 H), 6.90 (d, J = 8.7
Hz, 2H), 6.82 (d, J =
8.7 Hz, 2H), 5.01 (s, 2H), 3.90 (t, J = 6.2 Hz, 2H), 3.14 (t, J = 7.5 Hz, 2H),
2.64 (s, 3H), 1.84-
1.74 (m, 4H), 1.54-1.44 (m, 4H).
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10. 7-(4-H day-phenoxy)-1-(5-methyl-1.3.4-oxadiazol-2-yl)-heptan-l-one (66)
[0386] To a solution of 65.2 (30 mg, 0.076 mmol) in AcOEt (5 mL) was added 10%
Pd/C
(6 mg, 20% w/w) and the resulting suspension was stirred vigorously under
hydrogen
atmosphere, overnight at RT. The catalyst was removed by filtration through
Celite, and the
filtrate was evaporated under reduced pressure. The residue obtained was
purified by flash
column chromatography on silica gel (60% ethyl acetate-hexane) to give pure
compound 66
(0.016 g, 71% yield) as a white solid (melting point 134-135 C).
[0387] 66 was confirmed as follows: 'H NMR (500 MHz, CDC13) b 6.80-6.74 (m,
4H),
4.56 (br s, 1H), 3.89 (t, J = 6.5 Hz, 2H), 3.14 (t, J = 7.2 Hz, 2H), 2.64 (s,
3H), 1.84-1.74 (m,
4H), 1.54-1.44 (m, 4H).
Synthesis of a-Keto-oxadiazoles 73.1, 73.2, 74.1, and 74.2
[0388] a-Keto-oxadiazoles 73.1, 73,.2 74.1 and 74.2 were synthesized by a
method
depicted in Scheme 16 starting from 7-(phenoxy)heptanoic acid ethyl ester
(61.1), 7-[4-
(benzyloxy)phenoxy]heptanoic acid ethyl ester (61.2), and commercially
available methyl
glycolate (69).
Scheme 16
OO
R1 05000Et a R1 O" 5 N'OMe
Me
67 68
67.1=61.1:R1=H 68.1:R1=H
67.2=61.2=20.4: R1=OBn 68.2: R1=OBn
0
b O 0 N-N\\ OBn
HO OMe BnO~OMe C BnO~NHNH2 d ON
69 70 71 72
f for 73.1
0 or 0
e R1 O~N /N g for 73.2 1 O~N N
OOBn OAR2
73 74
73.1: R1 = H 74.1: R1 = H, R2 = OH
73.2: R1 = OBn 74.2: R1 = OH, R2 = OBn
[0389] Reagents and conditions for the steps in Scheme 16 were as follows:
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Step a: (MeO)MeNH-2'Cl-, n-BuLi, THF, -78"C, 15 min, then addition of 67, -78
C, 40 min,
85-87%; Step b: BnBr, Ag20, Et20, RT, 24 hours, 70%; Step c: H,NNH2'H2O, MeOH,
reflux, 3 hours; Step d: CH(OMe)3, p-TSA, reflux, 3 hours, 49% from 70; Step
e: n-BuLl,
MgBr2'Et2O, THF -78"C to -30"C, 2 hours, then addition of 68.1 or 68.2, -30 C
to 0 C, 4
hours, 53-55%; Step f: 1,4-cyclohexadiene, 10% Pd/C, AcOH/MeOH, 45C, 2 hours,
25%;
Step g: H2, 10% Pd/C, AcOEt, RT, overnight, 75%.
1. 7-Phenoxy-(N-methoxy-N -methyl)ptane-carboxamide (68.1)
[0390] The title compound was synthesized analogously to 68.2 (see description
below)
using dry N,O-dimethylhydroxyl amine hydrochloride (488 ing, 5 mmol) in
anhydrous THF
(40 mL), n-BuLi (2.5 M solution in hexanes, 4 mL, 10 mmol) and 67.2 (250 mg, 1
mmol).
The crude obtained after workup was chromatographed over a column of silica
gel, eluting
with 50% ethyl acetate-petroleum ether to afford 68.1 as a colorless liquid in
87% yield (230
mg).
[0391] 68.1 was confirmed as follows: 'H NMR (500 MHz, CDC13) b 7.27 (t, J =
8.0 Hz,
2H), 6.92 (t, J = 8.0 Hz, 1H), 6.89 (d, J = 8.0 Hz, 2H), 3.95 (t, J = 6.5 Hz,
2H), 3.68 (s, 3H),
3.18 (s, 3H), 2.43 (t, J = 7.5 Hz, 2H), 1.79 (quintet, J = 6.5 Hz, 2H), 1.67
(quintet, J = 7.5 Hz,
2H), 1.50 (quintet, J = 7.0 Hz, 2H), 1.42 (quintet, J = 7.0 Hz, 2H).
2. 7-[(4-Benzyloxy-phenoxy)-N-methoxy-N-methyll-heptane-carboxamide (68.2)
[0392] To a stirred suspension of N,O-dimethylhydroxyl amine hydrochloride
(dry, 680
mg, 7 mmol) in anhydrous THF (40 mL) at -78"C, under an argon atmosphere, was
added n-
BuLi (2.5 M solution in hexanes, 5.6 mL, 14 mmol) dropwise. The mixture was
stirred for
15 min after removing the dry ice/acetone bath (to ensure complete dissolution
of the salt),
cooled again to -78"C, and a solution of 67.1 (500 mg, 1.4 mmol) in anhydrous
THF (10 mL)
was added dropwise. The reaction mixture was stirred for an additional 40 min
at the same
temperature, diluted with aqueous NH4C1, and the resulting mixture warmed to
RT. The
organic layer was separated, and the aqueous layer extracted with ethyl
acetate (2 x 20 mL).
The combined organic layer was washed with brine (20 mL), dried over MgSO4,
and the
solvent evaporated under reduced pressure. The crude product was
chromatographed over a
column of silica gel, eluting with 50% ethyl acetate-petroleum ether to afford
68.2 as a white
solid (melting point 54-55"C) in 85% yield (440 mg).
[0393] 68.2 was confirmed as follows: 'H NMR (500 MHz, CDC13) 6 7.42 (d, J =
7.0 Hz,
2H), 7.37 (t, J = 7.0 Hz, 2H), 7.32 (t, J = 7.0 Hz, 1 H), 6.90 (d, J = 9.0 Hz,
2H), 6.81 (d, J =
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9.0 Hz,2H),5.01 (s,2H),3.90(t,J=6.2Hz,2H),3.68(s,3H),3.18(s,3H),2.43(t,J=7.5
Hz, 2H), 1.77 (quintet, J = 6.7 Hz, 2H), 1.67 (quintet, J = 7.7 Hz, 2H), 1.48
(quintet, J = 7.7
Hz, 2H), 1.40 (quintet, J = 7.5 Hz, 2H).
3. Methvl-2-benzyloxy-acetate (70)
[0394] To a stirred solution of methyl glycolate (2 g, 22.2 mmol) in anhydrous
diethyl
ether (100 mmL), at RT, under a nitrogen atmosphere, was added silver(I)oxide
(10.3 g, 44.4
mmol). The suspension was stirred for 15 min and benzyl bromide (4.5 g, 26.3
minol) was
added. The mixture was stirred at the same temperature for 24 hours, and the
insoluble
materials were removed by filtration through a short pad of celite. The
filtrate was
concentrated under reduced pressure, and the crude product chromatographed
over a column
of silica gel, eluting with 20% diethyl ether-petroleum ether to give 70, as a
colorless liquid
in 70% yield (2.8 g).
[0395] 70 was confirmed as follows: 'H NMR (500 MHz, CDC13) b 7.39-7.29 (in,
5H),
4.62 (s, 2H), 4.16 (s, 2H), 3.78 (s, 3H).
4. 2-Benzyloxy-acetic hydrazide (71)
[0396] A mixture of 70 (2.75 g, 15.3 mmol) in methanol (50 mL) and hydrazine
hydrate
(65% in water, 2.3 g, 30 mmol) was heated under reflux for 3 hours. The
reaction mixture
was concentrated under reduced pressure and the residue was diluted with
benzene. The
solvent was evaporated and the crude product was further dried under high
vacuum (6 hours)
to give 71 (2.75 g), as a light yellow waxy material, which was used in the
next step without
further purification.
[0397] 71 was confirmed as follows: ' H NMR (500 MHz, CDC13) b 7.72 (br s, 1
H, NH),
7.39-7.29 (m, 5H), 4.56 (s, 2H), 4.07 (s, 2H), 3.82 (br s, 2H, NH2).
5. 2-Benzyloxyrmethyl-1,3,4-oxadiazole (72)
[0398] To a mixture of 71, (2.7 g, 15 mmol) and trimethyl orthofonnate (5 mL)
was
added p-TSA, (anhydrous, 255 mg, 1.5 mmol). The mixture was refluxed for 3
hours, and
the excess trimethyl orthofozmate evaporated under reduced pressure. The crude
product was
purified over a column of silica gel, eluting with 30% acetone-petroleum ether
to give 72 as a
colorless liquid (1.4 g), in 49% yield (two steps).
[0399] 72 was confirmed as follows: 'H NMR (500 MHz, CDC13) 6 8.43 (s, 1H),
7.39-
7.31 (in, 5H), 4.77 (s, 2H), 4.64 (s, 2H).
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6. 7-(Phenoxy)-l -(5-benzylox r yl-1,3,4-oxadiazol-2-yl)-heptan-l-one (73.1)
[0400] The title compound was synthesized analogously to 73.2 (see description
below)
using 72 (190 mg, 1 mmol), n-BuLi (2.5 M solution in hexane, 0.4 mL, 1 mmol),
MgBrz,Et2O
(284 mg, 1.1 mmol) and 68.1 (132 mg, 0.5 mmol). The crude obtained after
workup was
chromatographed over a column of silica gel, eluting with 30% ethyl acetate-
petroleum ether
to give 73.1 as a white solid (melting point 61-63"C) in 53% yield (104 mg).
[0401] 73.1 was confirmed as follows: 'H NMR (500 MHz, CDC13) 6 7.38-7.32 (m,
5H),
7.27 (t, J = 7.0 Hz, 2H), 6.92 (t, J = 7.0 Hz, 1H), 6.90 (d, J = 7.0 Hz, 2H),
4.77 (s, 2H), 4.68
(s, 2H), 3.95 (t, J = 6.2 Hz, 2H), 3.16 (t, J = 7.2 Hz, 2H), 1.86-1.76 (m,
4H), 1.56-1.43 (m,
4H).
7. 7-(4-Benzyloxy_phenoxy)-1=(5-benzyloxyMethyl-1,3,4-oxadiazol-2-vl)-heptan-l-
one
73.2
[0402] To a stirred solution of 72 (380 mg, 2 mmol) in anhydrous THE (40 mL),
at -78 C,
under an argon atmosphere, was added n-BuLi (2.5 M solution in hexane, 0.8 mL,
2 mmol)
dropwise. Stirring was continued for 15 min at the same temperature, and then
MgBr2Et-'0
(568 mg, 2.2 mmol) was added. The mixture was warmed to -30 C over a 2 hour
period, and
then a solution of 68.2 (370mg, 1 mmol) in THE (10 mL) was added. The mixture
was
gradually warmed to 0"C and maintained at the same temperature for 4 hours.
The reaction
mixture was diluted with aqueous NH4C1 solution (20 mL) and ethyl acetate (50
ml) and
gradually warmed to RT. The organic layer was separated and the aqueous layer
was
extracted with ethyl acetate (2 x 20mL). The combined organic layer was washed
with brine
(30 mL), dried over MgS04, and the solvent evaporated under reduced pressure.
The crude
product was chromatographed over a column of silica gel, eluting with 30%
ethyl acetate-
petroleum ether to give 73.2 as a white solid (melting point 95-97"C) in 55%
yield (275 mg).
[0403] 73.2 was confirmed as follows: 'H NMR (500 MHz, CDC13) 6 7.42 (d, J =
8.0 Hz,
2H), 7.40-7.34 (in, 6H), 7.28-7.33 (in, 2H), 6.90 (d, J = 8.5 Hz, 2H), 6.81
(d, J = 8.5 Hz, 2H),
5.01 (s, 2H), 4.77 (s, 2H), 4.68 (s, 2H), 3.90 (t, J = 6.2 Hz, 2H), 3.16 (t, J
= 7.2 Hz, 2H), 1.86-
1.74 (in, 4H), 1.54-1.44 (rn, 4H).
8. 1 -(5-hydrox methyl-1.3.4-oxadiazol-2-yl)-7-phenoxy-heptan-l-one (74.1)
[0404] To a stirred suspension of 73.1 (80 mg, 0.2 mmol) and Pd/C (160 mg) in
AcOH/MeOH (1:10 mixture, 5 mL) at 45"C was added 1,4-cyclohexadiene (304 mng,
4 mmol)
over a period of 30 min. The mixture was stirred for an additional 2 hours at
the same
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temperature. The catalyst was removed by filtration through celite and the
filtrate was
evaporated under reduced pressure. The residue was purified through a column
of silica,
eluting with 45% ethyl acetate in petroleum ether to give 74.1 as a white
solid (melting point
83-85 C) in 25% yield (15 mg).
[0405] 74.1 was confirmed as follows: 1H NMR (400 MHz, CDC13) 6 7.27 (t, J =
7.0 Hz,
2H), 6.92 (t, J = 7.0 Hz, 1 H), 6.90 (d, J = 7.0 Hz, 2H), 4.88 (s, 2H), 3.95
(t, J = 6.5 Hz, 2H),
3.16 (t, J = 7.2 Hz, 2H), 2.56 (br s, 1H, OH), 1.88-1.74 (m, 4H), 1.59-1.44
(m, 4H).
9. 1-(5-benzyloxymethyl-1,3,4-oxadiazol-2-yl-7-(4-hydroxy-phenoxv)-heptan- l -
one
74.2
[0406] A mixture of 73.2 (50 mg, 0.1 mmol) and Pd/C (10 mg) in AcOEt (5 mL)
was
stirred vigorously under hydrogen overnight at RT. The catalyst was removed by
filtration
through celite and the filtrate was evaporated under reduced pressure. The
crude material
was purified through a column of silica gel, eluting with 45% ethyl acetate-
petroleum ether to
give 74.2 as a white solid in 75% yield (31 mg).
[0407] 74.2 was confirmed as follows: 'H NMR (500 MHz, CDC13) b 7.38-7.31 (m,
5H),
6.79-6.73 (m, 4H), 4.77 (s, 2H), 4.68 (s, 2H), 4.50 (br s, 1 H, OH), 3.90 (t,
J = 6.2 Hz, 2H),
3.15 (t, J = 7.2 Hz, 2H), 1.84-1.74 (m, 4H), 1.56-1.44 (m, 4H).
Synthesis of a-Keto-oxadiazoles 78 and 81
[0408] a-Keto-oxadiazoles 78 and 81 were synthesized by a method depicted in
Scheme
17 starting from commercially available 3-benzyloxybromobenzene (28) and 3-
anisaldehyde
(79).
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Scheme 17 /
O'~ O4
Br CN CHO HO N 0 N N
a b c d
OBn I \ I \ I \ I \
28 75 OBn 76 OBn 77 OBn 78 OBn
O4 04,
CHO HO N N O -N N
I d 1
LOMe OMe OMe
79 80 81
[0409] Reagents and conditions for the steps in Scheme 17 were as follows:
Step a: 3-cyanophenylboronic acid, Ba(OH2), Pd(PPh3)4, DME/H2O, reflux, 6
hours, 52%;
Step b: DIBAL-H, THF, -78"C, 1 hour, 65%; Step c: 63, n-BuLi, MgBr2'Et2O, THF -
78 C to
-45C, 2 hours, then addition of 76, -78"C to -45C, 2 hours, 59%; Step d: Dess-
Martin
periodinane, CH2Ch, 50 C, 2 hours, 80-82%; Step e: 63, n-BuLi, MgBr2'Et2O,
THF, -78 C to
-50 C, 2 hours, then addition of 79, -78 C, 2 hours, 57%.
1. 3-(3-Benzyloxy-phenyl)benzonitrile (75)
104101 A degassed mixture of' -benzyloxy-phenyl bromide (28) (0.2 g, 0.76
mmol), 3-
cyanophenylboronic acid (0.223 g, 1.52 mmol), barium hydroxide (0.285 g, 1.67
mmol),
Pd(PPh3)4 (0.088 g, 0.076 mmol), DME (5 mL) and H2O (3 ml-) was heated (80 C)
for 6
hours with vigorous stirring under an argon atmosphere. The reaction mixture
was cooled to
RT, diluted with ethyl acetate, and filtered through a plug of celite. The
filtrate was diluted
with brine; the organic phase was separated, dried (_MgSO4), and concentrated
in vacuo. The
residue obtained was purified by flash column chromatography (20% diethyl
ether-hexane) to
give 75 (0.130 g, 60% yield) as a viscous liquid.
[0411] 75 was confirmed as follows: 'H NMR (500 MHz, CDC13) 6 7.85 (t, J = 2.5
Hz,
IH),7.78(dt,J=7.5Hz,J=1.5Hz,1H),7.63(dt,J=8.0Hz, J = 1.5 Hz, IH), 7.53 (t, J =
8.0 Hz, 1H), 7.46 (d, J = 7.5 Hz, 2H), 7.44-7.37 (m, 3H), 7.35 (t, J = 7.0 Hz,
1H), 7.18-7.14
(m, 2H), 7.02 (dd, J = 8.5 Hz, J = 2.5 Hz, IH), 5.17 (s, 2H).
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2. 3-(3-Benzyloxy-phenyl)benzaldehyde (76)
[0412] To a stirred solution of 75 (0.12 g, 0.42 mmol) in anhydrous THE (10
mL) at -
78 C, under a nitrogen atmosphere was added di 1 sobutyl aluminum hydride (0.5
mL, 0.5
mmol, using a 1 M solution in hexane) dropwise. The reaction mixture was
stirred at the
same temperature for 1 hour, and then quenched by dropwise addition of
potassium sodium
tartrate (10% solution in water). The resulting mixture was warmed to RT,
diluted with
diethyl ether (20 mL), and stirred vigorously for 1 hour. The organic phase
was separated
and the aqueous phase was extracted with diethyl ether. The combined organic
layer was
washed with brine, dried (MgSO4), and evaporated under reduced pressure. The
residue
obtained was purified by flash column chromatography on silica gel (20%
diethyl ether-
hexane) to give 76 (0.091 g, 75% yield) as a viscous liquid.
[0413] 76 was confirmed as follows: 'H NMR (500 MHz, CDC13) 6 10.08 (s, 1H),
8.09
(t, J = 1.5 Hz, 1 H), 7.85 (dt, J = 7.5 Hz, J = 1.5 Hz, 2H), 7.60 (t, J = 7.7
Hz, 1 H), 7.47 (d, J =
7.5 Hz, 2H), 7.44-7.32 (m, 3H), 7.35 (t, J = 7.5 Hz, 1H), 7.27-7.21 (m, 2H),
7.02 (dd, J = 7.7
Hz, J = 2.0 Hz, I H), 5.14 (s, 2H).
3. 1-(3'-Benzyloxy 1,1'-biphenyl-3-yl)-1-(5-methyl-1,3,4-oxadiazol-2-yl)-
methanol (77)
[0414] To a stirred solution of 63 (0.118 g, 1.5 mmol), in dry THE (5 mL), at -
78 C,
under a nitrogen atmosphere, was added n-BuLi (0.6 mL, 1.5 mmol, using a 2.5M
solution in
hexane) dropwise. Stirring continued for 10 min at -78 C, and then MgBr2'Et22O
(0.4 g, 1.5
mmol) was added. The resulting mixture was warmed to -45 C over a 2 hour
period, cooled
back to -78 C, and a solution of 76 (0.081 g, 0.28 mmol) in dry THE (5 mL) was
added
dropwise. Following the addition, the reaction mixture was warmed to -45 C
over a 2 hour
period and then diluted with aqueous NH4CI solution (5 mL) and AcOEt (20 mL).
The
resulting mixture was gradually warmed to RT, the organic phase was separated,
and the
aqueous phase extracted with AcOEt. The combined organic layer was washed with
brine,
dried (MgS04), and evaporated under reduced pressure. The residue obtained was
purified
by flash column chromatography on silica gel (75% ethyl acetate-hexane) to
give 77 (0.052 g,
50% yield) as a colorless viscous liquid.
[0415] 77 was confirmed as follows: 'H NMR (500 MHz, CDC13) 6 7.69 (m as br s,
1H),
7.59-7.56 (m, 1H), 7.47-7.45 (m, 4H), 7.40 (t, J = 7.0 Hz, 2H), 7.37-7.32 (m,
2H), 7.20 (t, J =
2.0 Hz, I H), 7.18 (d J = 8.0 Hz, I H), 6.98 (dd, J = 8.5 Hz, J = 2.0 Hz, I
H), 6.08 (s, I H), 5.12
(s, 2H), 3.22 (br s, 1H), 2.45, (s, 3H).
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4. 1-(3'-Benzyloxy-1,1'-biphenyl-3-yl)-1-(5-methyl-1,3,4-oxadiazol-2-yl)-
ketone (78)
[0416] To a solution of 77 (45 mg, 0.12 mmol) in wet CH2C12 (5 mL) at RT,
under
nitrogen, was added Dess-Martin periodinane (102 mg, 0.24 mmol) and the
resulting
suspension stirred for 2 hours at 50 C. The reaction mixture was cooled to RT,
diluted with
Na2S2O3 (10% in H2O) and saturated aqueous NaHCO3 solution, and the organic
phase was
separated. The aqueous layer was extracted with AcOEt and the combined organic
layer was
washed with brine, dried MgSO4, and evaporated under reduced pressure. The
residue
obtained was purified by flash column chromatography on silica gel (60% ethyl
acetate-
hexane) to give 78 (35.52 mg, 80% yield) as a white solid (melting point 97-99
C).
[0417] 78 was confirmed as follows: 'H NMR (500 MHz, CDC13) b 8.70 (t, J = 2.0
Hz,
I H), 8.54 (d, J = 8.0 Hz, 1H),7.90(d,J=8.0Hz, 1H),7.62(t,J=8.0Hz,
1H),7.48(d,J=
7.5 Hz, 2H), 7.42-7.40 (m, 3H), 7.34 (t, J = 7.5 Hz, I H), 7.27-7.25 (in, 2H),
7.01(dd, J = 7.0
Hz, J = 2.0 Hz, 1H), 5.15 (s, 2H), 2.71 (s, 3H).
5. 1 -(3-Methoxy-phenyl)-I-(5-inethyl -1,3,4-oxadiazol-2-yl)-methanol (80)
[0418] The synthesis was carried out analogous to the preparation of 77 using
79 (0.14 g,
1.03 mmol) and 63 (0.29 g, 3.45 mmol). Purification by flash column
chromatography on
silica gel gave compound 80 (0.12 g, 53.4% yield) as a viscous liquid.
[0419] 80 was confirmed as follows: 'H NMR (500 MHz, CDC13) 6 7.30 (t, J = 7.5
Hz,
1 H), 7.06-7.02 (1n, 2H), 6.90 (dd, J = 7.5 Hz, J = 2.5 Hz, 1 H), 6.05 (d, J =
5.0 Hz, 1 H), 3.83
(s, 3H), 3.67 (d, J = 5.0 Hz, 1H), 2.49 (s, 3H).
6. 1-(3-Methoxy_phenyl)-1-(5-methyl-1,3,4-oxadiazol-2-V)-ketone (81)
[0420] 1-(3-Methoxy-phenyl)-1-(5-methyl -1,3,4-oxadiazol-2-yl)-ketone (81) was
synthesized as in 78 using 80 (0.1 g, 0.454 mmol) and Dess-Martin periodinane
(0.38 g, 0.9
nunol) in wet CH2C12 (10 mL). Purification by flash column chromatography on
silica gel
gave compound 81 (0.080 g, 82% yield) as a viscous liquid.
[0421] 81 was confirmed as follows: 'H NMR (500 MHz, CDC13) b 8.10 (dt, J =
7.5 Hz, J
= 1.5 Hz, 1H), 7.99 (t, J = 1.5 Hz, 1H), 7.47 (t, J = 7.5 Hz, 1H), 7.24 (dd, J
= 7.5 Hz, J = 1.5
Hz, IH), 390 (s, 3H), 2.70 (s, 3H).
Synthesis of a-Keto-oxadiazole 81.1
[0422] a-Keto-oxadiazole 81.1 was synthesized by a method depicted in Scheme
18.
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Scheme 18
Ph Ph 0 b Ph 0 c
Ph O
a
\
80a
80b OEt 80c OEt 80d N-O
d Ph
81.1 N
[0423] Reagents and conditions for the steps in Scheme 18 were as follows:
Step a: NaH,
(EtO)2POCH2CO2Et, 0 C - RT, 2 hours, 91%; Step b: H2, Pd/C, 50 p.s.i., RT, 6
hours, 95%;
Step c: Me(OMe)NH.HCI, i-Pr-MgCI, THF, -20 C to 0 C 87%; Step d: 63, n-BuLi,
MgBr2
Et20, THF, -78 C to -50 C, 2 hours, then addition of 80d -30 to 0 C, 4 hours,
56%.
1. Eth lphenylc clohexylidene) acetate 80b
[0424] To a solution of triethyl phosphonoacetate (3.5 equivl) in anhydrous
THF, at 0 C
under an argon atmosphere, was added sodium hydride (3.5 equiv 60% dispersion
in mineral
oil). The suspension was stirred for 15 min at the same temperature, and a
solution of 80a (1
equiv) in anhydrous THF was added dropwise. The reaction was gradually warmed
to RT
and stirred for additional 2 hours and upon completion was quenched by the
addition of
saturated aqueous NH4C1. The mixture diluted with diethyl ether (100 mL) and
the aqueous
phase extracted with diethyl ether. The combined organic layer was washed with
brine, dried
over MgS04, and the solvent was evaporated under reduced pressure. The residue
was
purified by flash column chromatography on silica gel using (20% EtOAc:Heaxne)
to 80b as
a colorless liquid in 91 % yield.
[0425] 80b was confirmed as follows: 'H NMR (500 MHz, CDC13) 6 7.33-7.30 (m,
2H),
7.40-7.20 (m, 3H), 5.79 (s, 1H), 4.19 (q, J = 7.0 Hz, 2H), 3.99 (d, J = 15.0
Hz, IH), 2.81 (dt, J
=15.0Hz,J=3.5Hz,1H),2.39(dq,J=13.2Hz,J=3.5Hz,2H),2.07(dq,J=13.2Hz,J=
3.5 Hz, 2H), 1.66 (dq, J = 13.2 Hz, J = 4.0 Hz, 2H), 1.31 (t, J = 7.0 Hz, 3H).
2. Ethvl-2-(4-phenylcyclohexyl)acetate (80c)
[0426] A mixture of 80b (1 equiv.) and 10% Pd/C (0.16 equiv) in EtOH was
placed in a
Parr apparatus (Parr Instrument Co, Moline, IL) and treated with hydrogen at
50 psi for 6
hours. The catalyst was removed by filtration through a pad of celite and the
filtrate was
evaporated under reduced pressure to give 80c as a colorless liquid in 95%
yield, used in the
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next step without further purification.
[0427] 80c was confirmed as follows: 'H NMR (500 MHz, CDC13) 8 7.34-7.30 (m,
2H),
7.28-7.20 (in, 3H), 4.18 (q, J = 7.2 Hz, 2H), 2.53-2.46 (in, 2H), 2.70 (d, J =
6.5 Hz, 2H), 1.95-
1.86 (in, 5H),), 1.55 (dq, J = 12.5 Hz, J = 3.5 Hz, 2H), 1.30 (t, J = 7.2 Hz,
3H), 1.21 (dq, J =
12.5, J = 2Hz, 2H).
3. N-Methoxy N' meth4 phenyls clollexyl)acetamide (80d)
[0428] N-Methoxy-N'-methyl-2-(4-phenylcyclohexyl)acetamide (80d) was prepared
as
described for 68 (scheme 16).
[0429] 80d was confirmed as follows: 'H NMR (500 MHz, CDC13) d 7.33-7.29 (m,
2H),
7.23-7.18 (m, 3H), 3.72 (s, 3H), 3.22 (s, 3H), 2.49 (dt, J = 14.5 Hz, J = 4.5
Hz, 1 H), 2.39 (d, J
= 6.5 Hz, 2H), 1.96-1.90 (m, 5H), 1.55 (dq, J = 13.2 Hz, J = 3.0 Hz, 2H), 1.22-
1.16 (m, 2H).
4. 1-(5-Methyl-1,3,4-oxadiazol-2-yl -2-(4-phenvlc cl~yl)ethanone (81.1)
[0430] 1-(5-Methyl-1,3,4-oxadiazol-2-yl)-2-(4-phenylcyclohexyl)ethanone 81.1
was
synthe-sized as described for 73 (scheme 16).
[0431] 81.1 was confirmed as follows: 'H NMR (500 MHz, CDC13) 6 7.32-7.28 (in,
2H),
7.23-7.17 (in, 3H), 3.07 (d, J = 7.0 Hz, 2H), 2.65 (s, 3H), 2.49 (tt, J = 13.5
Hz, J = 4.5 Hz,
I H), 2.18-2.08 (m, I H)., 1.92 (d, J = 11.5 Hz, 4H), 1.55-1.48 (m, 2H) 1.31-
1.22 (m, 2H).
Synthesis of saccharin analogs (83.1 - 83.9 and 84)
[0432] Saccharin analogs 83.1, 83.2, 83.3, 83.4, 83.5, 83.6, 83.7, 83.8, 83.9
and 84
(shown in Scheme 19) were synthesized by a method depicted in Scheme 19
starting from
commercially available saccharin (82) and the appropriate bromide.
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Scheme 19
0 0
a or b
NH N-R
~- O 0~~0
82 83
83.1:R Ph
OPh
83.2: R =
83.3: R = O / OBn
83.4: R =V'---\OPh
83.5: R = OPh
Me
$3.6:R= O
83.7: R =
CI
83.8: R
83.9: R O N02
=
0 0
N 0 OBn c \ N--,,~i0 OH
S"O
83.3 84
[04331 Reagents and conditions for the steps in Scheme 19 were as follows:
Step a: (i) NaH, THF, 0C to RT, 1 hour, (ii) RBr, DMF, 80C, 4 hours, 66-67%;
Step b: (i)
NaH, DMF, RT, 15 min, (ii) RBr, DMF, microwave, 150C, 10 min, 45-65%; Step c:
1,4-
cyclohexadiene, Pd/C, EtOH, 50C, 2 hours, 56%.
1. N-(Phen. ly methyl)saccharin (83.1)
[04341 To a stirred solution of saccharin 82 (0.154 g, 0.75 mmol) in anhydrous
THF (10
mL) at 0"C, under nitrogen atmosphere was added NaH (0.019 g, 0.8 mmol, using
a 60%
dispersion in mineral oil) and the resulting slurry was gradually warmed to RT
over 1 hour
period . Solvent was removed under reduced pressure, and the saccharin sodium
salt was
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dissolved in anhydrous DMF (5 mL). To this solution, was added a solution of
benzyl
bromide (0.051 g, 0.3 mmol) in DMF (5 mL), under nitrogen, at RT, and the
mixture warmed
to 80 C and stirred for 4 hours. The reaction mixture was cooled to RT and
diluted with
dropwise addition of water (5 mL) and AcOEt (20 mL). The organic layer was
separated and
the aqueous layer extracted with AcOEt. The combined organic layer was washed
with brine,
dried (MgSO4), and the solvent removed in hacuo. The residue was purified by
flash column
chromatography on silica gel (50% diethyl ether-hexane) to give 83.1 (0.054g,
66% yield), as
a white solid (melting point 106-108C).
[0435] 83.1 was confirmed as follows: 1H NMR (500 MHz, CDC13) 6 8.06 (d, J =
7.0 Hz,
I H), 7.93 (d, J = 7.0 Hz, I H), 7.87 (td, J = 7.0 Hz, J = 1.2 Hz, I H), 7.83
(td, J = 7.0 Hz, J =
1.2 Hz, 1H), 7.51 (d, J = 7.5 Hz, 2H), 7.36 (t, J = 7.5 Hz, 2H), 7.31 (t, J =
7.0 Hz, 1H), 4.91
(s, 2H).
2. N-(4-Phenoxy-butyl)saccharin (83.2)
[0436] The synthesis was carried out analogous to the preparation of 83.1
using 82 (0.23
g, 1.25 mmol), NaH (0.030 g, 1.25 mmol) and 4-phenoxy-butyl bromide (0.115 g,
0.5 mmol)
in DMF (5 mL). Purification by flash column chromatography on silica gel gave
83.2 (0.1 g,
67% yield) as a white solid (melting point 92-94"C).
[0437] 83.2 was confirmed as follows: 1H NMR (500 MHz, CDC13) 6 8.07 (d, J =
7.0 Hz,
I H), 7.93 (d, J = 7.0 Hz, I H), 7.87 (td, J = 7.0 Hz, J = 1.2 Hz, 1 H), 7.83
(td, J = 7.0 Hz, J =
1.2 Hz, 1 H), 7.27 (t, J = 7.5 Hz, 2H), 6.93 (t, J = 7.5 Hz, 1 H), 6.90 (d, J
= 7.5 Hz, 2H), 4.02
(t, J = 6.5 Hz, 2H), 3.88 (t, J = 7.2 Hz, 2H), 2.07 (quintet, J = 6.9 Hz, 2H),
1.92 (quintet, J =
6.9Hz, 2H).
3. N-[4-(4-Benzyloxy phenoxy)-butyl] saccharin (83.3)
[0438] The synthesis was carried out analogous to the preparation of 83.1
using 82
(0.307g, 1.5 mmol), NaH (0.036 g, 1.5 mmol) and 4-(4-benzyloxy-phenoxy)-butyl
bromide
(0.2 g, 0.6 mmol) in DMF (5 mL). Purification by flash column chromatography
on silica gel
gave 83.3 (0.150 g, 66% yield) as a white solid (melting point 82-84C).
[0439] 83.3 was confirmed as follows: 'H NMR (500 MHz, CDCI3) b 8.06 (d, J =
7.0 Hz,
I H), 7.92 (d, J = 7.0 Hz, IH), 7.87 (td, J = 7.0 Hz, J = 1.2 Hz, I H), 7.83
(td, J = 7.0 Hz, J =
1.2 Hz, I H), 7.42 (d, J = 7.5 Hz, 2H), 7.37 (t, J = 7.5 Hz, 2H), 7.31 (t, J =
7.5 Hz, 1 H), 6.89
(d, J = 9.0 Hz, 2H), 6.82 (d, J = 9.0 Hz, 2H), 5.00 (s, 2H), 3.97 (t, J = 6.4
Hz, 2H), 3.86 (t, J =
7.2 Hz, 2H), 2.05 (quintet, J = 6.9 Hz, 2H), 1.89 (quintet, J = 6.9 Hz, 2H).
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4. N-(3-Phenoxypropyl)saccharin (83.4)
[0440] The title compound was synthesized analogously to 83.8 (see
experimental
below), using a solution of saccharin (92 mg, 0.5 mmol) in DMF (anhydrous, 4
mL), NaH
(60% dispersion in mineral oil, 21 mg, 0.52 mmol) and a solution of 3-
phenoxypropyl
bromide (130 mg, 0.6 mmol) in anhydrous DMF (1 mL). The crude obtained after
workup
was purified by flash column chromatography on silica gel (25% ethyl acetate
petroleum
ether) to give 83.4 as a white solid (melting point 83-86"C) in 65% yield (130
mg).
[0441] 83.4 was confirmed as follows: 'H NMR (500 MHz, CDC13) d 8.08 (dd, J =
7.5
Hz, J= 1.5 Hz, 1H),7.95(dd,J=7.5Hz,J=1.5Hz1H), 7.89 (td, J = 7.5 Hz, J = 1.5
Hz,
I H), 7.85 (td, J = 7.5 Hz, J = 1.5 Hz, I H), 7.30 (t, J = 8.0 Hz, 2H), 6.97
(t, J = 8.0 Hz, I H),
6.93 (d, J = 8.0 Hz, 2H), 4.11 (t, J= 6.2 Hz,2H),4.04(t,3=7.1
Hz,2H),2.36(quintet,J=
7.5 Hz, 2H).
5. N-(6-Phenoxyhexyl)saccharin (83.5)
[0442] The title compound was synthesized analogously to 83.8 (see description
below)
using a solution of saccharin (92 mg, 0.5 mmol) in anhydrous DMF (4 i mL), NaH
(60%
dispersion in mineral oil, 21 mg, 0.52 mmol), and a solution of 6-phenoxybutyl
bromide (154
mg, 0.6 mmol) in DMF (anhydrous, 1 mL). The crude product obtained after
workup was
purified by flash column chromatography on silica gel (20% ethyl acetate-
petroleum ether) to
give 83.5 as a white solid (melting point 64-66 C) in 50% yield (90 mg).
[0443] 83.5 was confirmed as follows: 'H NMR (500 MHz, CDC13) 6 8.07 (dd, J =
7.5
Hz,J=1.5Hz,1H),7.93(dd,J=7.5Hz,J=1.5Hz 1H), 7.88 (td, J = 7.5 Hz, J = 1.5 Hz,
1 H), 7.84 (td, J = 7.5 Hz, J = 1.5 Hz, 1 H), 7.28 (t, J = 7.5 Hz, 2H), 6.94
(t, J = 7.5 Hz, 1 H),
6.90 (d, J = 7.5 Hz, 2H), 3.98 (t, J = 6.5 Hz, 2H), 3.81 (t, J = 7.5 Hz, 2H),
1.91 (quintet, J =
7.2 Hz, 2H), 1.83 (quintet, J = 7.2 Hz, 2H), 1.61-1.48 (m, 4H).
6. N-[4- 3-Methyl-phenoxy)-butyl]saccharin (83.6)
[0444] The title compound was synthesized analogously to 83.8 (see description
below)
using a solution of saccharin (92 mg, 0.5 mmol) in anhydrous DMF (4 mL), NaH
(60%
dispersion in mineral oil, 21 mg, 0.52 mmol) and a solution of 1-(4-
bromobutoxy)-3-
methylbenzene (146 mg, 0.6 mmol) in DMF (anhydrous, 1 mL). The crude product
obtained
after workup was purified by flash column chromatography on silica gel (25%
ethyl acetate-
petroleum ether) to give 83.6 as a viscous liquid in 55% yield (95 mg).
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[0445] 83.6 was confirmed as follows: 'H NMR (500 MHz, CDC13) 8 8.08 (dd, J =
7.5
Hz,J=1.5Hz,1H),7.94(dd,J=7.5Hz,J=1.5HzIH),7.88(td, J= 7.5 Hz, J= 1.5 Hz,
I H), 7.85 (td, J = 7.5 Hz, J = 1.5 Hz, I H), 7.17 (t, J = 7.2 Hz, I H), 6.77
(dd, J = 7.2 Hz, 1.5
Hz, I H), 6.74 (t, J = 1.5 Hz, I H), 6.72 (dd, J = 7.2 Hz, J = 1.5 Hz, I H),
4.03 (t, J = 6.5 Hz,
2H). 3.89 (t, J = 7.5 Hz, 2H), 2.34 (s, 3H), 2.08 (quintet, J = 7.5 Hz, 2H),
1.92 (quintet, J =
7.0 Hz, 2H).
7. N-14-(4-Chloro-phenoxy)-butyl] saccharin (83.7)
[04461 The title compound was synthesized analogously to 83.8 (see description
below)
using a solution of saccharin (92 mg, 0.5 mmol) in anhydrous DMF (4 mL), NaH
(60%
dispersion in mineral oil, 21 mg, 0.52 mmol) and a solution of 1-(4-
bromobutoxy)-4-
chlorobenzene (158 mg, 0.6 mmol) in anhydrous DMF (1 mL). The crude product
obtained
after workup was purified by flash column chromatography on silica gel (25%
ethyl acetate-
petroleum ether) to give 83.7 as a white solid (in p 85-88 C) in 57% yield
(104 mg).
[0447] 83.7 was confirmed as follows: 'H NMR (500 MHz, CDC13) 6 8.08 (d, J =
7.2 Hz,
1H),7.94(d,J=7.2Hz,1H),7.89(td,J=7.2Hz,J=1.2Hz,IH),7.85(td,3= 7.2 Hz, J =
1.2 Hz, 1H),7.23(d,J=8.7Hz,2H),6.84(d,J=8.7Hz,2H),4.01 (t, J= 6.2 Hz, 2H),
3.89
(t, J = 7.5 Hz, 2H), 2.07 (quintet, J = 7.5 Hz, 2H), 1.92 (quintet, J = 8.2
Hz, 2H).
8. N-(6-tert-Butyldimethvlsilyloxy-hexyl)saccharin (83.8)
[0448] To a solution of saccharin (92 mg, 0.5 mmol) in anhydrous DMF (4 mL),
at RT,
under a nitrogen atmosphere, was added NaH (60% dispersion in mineral oil, 21
mg, 0.52
mmol). The mixture was stirred at the same temperature for additional 15 min,
a solution of
(6-bromohexyloxy)-tort-butyldimethylsilane (177 m(,, 0.6 mmol) in DMF (1 mL)
was added,
and the resulting mixture microwaved at 150 C for 10 min. The reaction mixture
was cooled
to RT and diluted with water (5 mL) and AcOEt (10 mL). The organic layer was
separated,
and the aqueous layer extracted with AcOEt (2 x 10 mL). The combined organic
layer was
washed with brine, dried (MgSO4), and the solvent removed in vacuum. The
residue was
purified by flash column chromatography on silica gel (20% ethyl acetate
petroleum ether) to
give 83.8 (89 mg. 45% yield), as a viscous liquid.
[0449] 83.8 was confirmed as follows: 'H NMR (400 MHz, CDC13) b 8.07 (dd, J =
7.4
Hz, J = 1.5 Hz, I H), 7.93 (dd, J = 7.4 Hz, J = 1.5 Hz I H), 7.88 (td, J = 7.4
Hz, J = 1.5 Hz,
I H), 7.84 (td, J = 7.4 Hz, J = 1.5 Hz, 1 H), 3.79 (t, J = 7.5 Hz, 2H), 3.62
(t, J = 6.4 Hz, 2H),
1.88 (quintet, J = 7.3 Hz, 2H), 1,55 (quintet, J = 6.7 Hz, 2H), 1.50-1.34 (m,
4H), 0.91 (s, 9H),
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0.07 (s, 6H).
9. N-14-(3-Nitro-phenoxy)-butyllsaccharin (83.9)
[0450] The title compound was synthesized analogously to 83.8, using a
solution of
saccharin (92 ing, 0.5 mmol) in anhydrous DMF (4 mL), NaH (60% dispersion in
mineral oil,
21 mg, 0.52 mmol) and a solution of 1-(4-bromobutoxy)-3-nitrobenzene (164 mg,
0.6 mmol)
in anhydrous DMF (1 mL). The crude product obtained after workup was purified
by flash
column chromatography on silica gel (25% ethyl acetate-petroleum ether) to
give 83.9 as a
white solid (m p 87-89 C) in 55% yield (95 mg).
[0451] 83.9 was confirmed as follows: 'H NMR (500 MHz, CDC13) 6 8.09 (dd, J =
7.2
Hz, J = 1.5 Hz, 1H), 7.95 (dd, J = 7.2 Hz, J = 1.5 Hz 1H), 7.90 (td, J = 7.2
Hz, J = 1.5 Hz,
1H),7.86(td,J=7.2Hz,J=1.5Hz, 1H),7.83(dd,J=8.0Hz,J=1.8Hz, 1H),7.74(t,J=
1.8 Hz,1H),7.43(t,J=8.0Hz, IH),7.24(dd,J=8.0Hz,J=1.8Hz,1H),4.12(t,J=6.2
Hz, 2H), 3.91 (t, J = 7.0 Hz, 2H), 2.10 (quintet, J = 7.5 Hz, 2H), 1.98
(quintet, J = 7.2 Hz,
2H).
10. N-14-(4-Hydroxy-phenoxy)-butyllsaccharin (84)
104521 To a stirred solution of 83.3 (0.1 g, 0.23 mmol) in EtOH (5 mL) was
added 10%
Pd/C (0.1 g, 100% w/w) and 1,4-cyclohexadiene (92 mg, 1.15 mmol) and the
resulting
suspension was stirred vigorously at 50"C for 2 hours. The reaction mixture
was cooled to
RT, the catalyst was removed by filtration through Celite, and the filtrate
was evaporated
under reduced pressure. The residue was purified by flash column
chromatography on silica
gel (60% diethyl ether-hexane) to give 84 (0.044 g, 56% yield) as a white
solid (melting point
107-109 Q.
[0453] 84 was confirmed as follows: 'H NMR (500 MHz, CDC13) b 8.06 (d, J = 7.0
Hz,
I H), 7.92 (d, J = 7.0 Hz, I H), 7.87 (td, J = 7.0 Hz, J = 1.2 Hz, I H), 7.83
(td, J = 7.0 Hz, J =
1.2 Hz, 1 H), 6.79 (d, J = 9.0 Hz, 2H), 6.74 (d, J = 9.0 Hz, 2H), 4.3 8 (br s,
1 H), 3.96 (t, J = 6.4
Hz, 2H), 3.89 (t, J = 7.2 Hz, 2H), 2.05 (quintet, J = 6.9 Hz, 2H), 1.89
(quintet, J = 6.9 Hz,
2H).
Synthesis of a-keto-esters and a,a-difluoromethylene-ketones
[0454] a-Keto-esters 87.1-4 and 87.7 as well as a,a-difluoromethylene-ketones
89.1,
89.2, 89.4, and 89.7-14 were synthesized by the methods depicted in Scheme 20.
3-
Benzyloxyphenol (85.1), 4-benzyloxyphenol (85.5), 2-benzyloxyphenol (85.6), 4-
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phenoxybutyl bromide (86.2), 5-phenoxypentyl bromide (86.4), 6-phenoxyhexyl
bromide
(86.7), 3-methyl-phenyl magnesium bromide, 2-bromopyridine, and 3-
bromopyridine were
commercially available materials. The 2-methyl-oxadiazole (63), 2-
bromopyridine, and 3-
bromopyridine were served as precursors for the preparation of the respective
organolithium
reagent using commercially available n-BuLi.
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Scheme 20
a b _ 0 c
R, O11 Rt O nBr R, / \ _, OyJ/
R2 R3 R2 R3 R2 R3 0
85 86 87
85.1: R, = H, R2 = OBn, R3 = H 86.1: R, = H, R2 = OBn, R3 = H, n = 4
87.1:R,=H,R2=OBn,R3=H,n4
85.5: R, = OBn, R2 = H, R3 = H 86.2: R, = H, R2 = H, R3 = H, n = 4 87.2: R, =
H, R2 = H, R3 = H, n = 4
85.6:R,=H,R2=H,R3=0Bn 86.3:R,=OBn,R2=H,R3=H,n=4 87.3: R, = OBn, R2 = H, R3 =
H, n = 4
86.4: R,= H, R2= H, R3 = H, n = 5 87.4: R,= H, R2 = H, R3=H,n=5
86.5: R, = OBn, R2 = H, R3 = H, n = 2 87.7: R,= H, R2 = H, R3=H,n=6
86.6: R, = H, R2 = H, R3 = OBn, n = 4
86.7:R,=H,R2=H, R3=H,n=6
R, p- OE n d R, 0F F
Ra
R2 R3 n 0 R2 R3 n 0
88 89
88.1: R,= H, R2 = OBn, R3 = H, n = 4 89.1: R,= H, R2 = OBn, R3 = H, R4 = Me, n
= 4
88.2: R,= H, R2= H, R3= H, n = 4 89.2: R,= H, R2 = H, R3= H, R4= Me,n=4
88.4: R,= H, R2 = H, R3=H,n=5 89.4: R,= H, R2 = H, R3 = H, R4 = Me, n = 5
88.7:R,=H,R2=H,R3=H,n=6 N-N
89.7:R,=H,R2=H,R3=H,R4=\/`0/-CH3'n=6
89.8:R,=H,R2=H,R3=H,R4=s' Me n=4
89.9:R,=H,R2=H,R3=H,R4=' N n=4
89.10: R,=H, R2=H, R3 = H, R4=' // N,n=4
89.11: R,= H, R2=OBn,R3=H,R4= IN ,n=4
N-N
89.12: R, = H, R2 = H, R3 = H, R4
=\~0OH3,n=4
N-N\1
89.13: R, = H, R2 = OBn, R3 = H, R4 = \~O~CH ' n = 4
3
89.14:R,=H,R2=0Bn,R3=H,R4= N ,n=4
[0455] Reagents and conditions for the steps in Scheme 20 were as follows:
Step a: Br-
(CH2)õ-Br, K2C03, acetone or MeCN, reflux, 10-12 hours, 68-74% for n = 4, 5, 6
or NaH,
DMF, RT to 80C, 6 hours, 64% for n = 2; Step b: Mg, THF, RT to gentle reflux,
then
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addition to (COOEt)2, THF, -78 C to 10 C, 1 hour, 45-65%; Step c: DAST, CHC13,
reflux, 3
hours, 72-88% or DAST CHC13, microwave, 100 C, 300 W, 3-5 min, 74-86%; Step d:
R4Li,
THF or Et2O, -78 C to RT, 1-2 hours, 65-78%.
1. Bromides (86)
[0456] A mixture of phenol derivative 85 (1 equiv.), a,o-dibromoalkane (1.5
equiv.) and
anhydrous potassium carbonate was stirred under refluxed in dry acetone or
acetonitrile for
10-12 hours, cooled to RT, and solid materials were filtered off. The filtrate
was evaporated,
water was added to the residue, and the mixture was extracted with diethyl
ether. The ethereal
layer was washed with 10% sodium hydroxide solution, water, brine, dried
(MgSO4), and
concentrated under reduced pressure. Purification by flash column
chromatography on silica
gel (diethyl ether-hexane) gave compound 86 as colorless viscous oil in 68-74%
yields.
2. Bromide 86.5
[0457] A mixture of 4-benzyloxy-phenol 85.5 (1 equiv.) and NaH in anhydrous
dimethylformamide was stirred at RT for 15 min under argon. To this mixture
was added
1,2-dibromoethane (1.5 equiv.) and stirring was continued at 80"C for 6 hours.
The reaction
mixture was cooled to RT, diluted with water and extracted with diethyl ether.
The ethereal
layer was washed with water and brine, dried (MgSO4), and concentrated under
reduced
pressure. Purification by flash column chromatography on silica gel (diethyl
ether-hexane)
gave product 86.5 in 64% yield.
3. Selected data of synthesized bromides (86)
1-Bromo-4-[3-(benzyloxy)phenoxy]butane (86.1)
[0458] 86.1 was confirmed as follows: IH NMR (500 MHz, CDC13) b 7.43 (d, J =
7.6 Hz,
2H),7.39(t,J=7.6Hz,2H),7.32(t,J=7.6Hz,IH),7.17(t,J=8.5 Hz,1H),6.58(dd,J=
8.5 Hz, J = 2.5 Hz, I H), 6.54 (t, J = 2.5 Hz, 1 H), 6.50 (dd, J = 8.5 Hz, J =
2.5 Hz, 1 H), 5.04
(s, 2H), 3.97 (t, J = 6.3 Hz, 2H), 3.48 (t, J = 6.5 Hz, 2H), 2.06 (m, 2H),
1.93 (m, 2H).
1-Bromo-2-[4-(benzyloxy)phenoxy]ethane (86.5)
[0459] 86.5 was confirmed as follows: 'H NMR (500 MHz, CDC13) 6 7.43 (d, J =
7.3 Hz,
2H), 7.38 (t, J = 7.3 Hz, 2H), 7.32 (t, J = 7.3 Hz, 1H), 6.92 (d, J = 8.5 Hz,
2H), 6.85 (d, J =
8.5 Hz, 2H), 5.07 (s, 2H), 4.24 (t, J = 6.5 Hz, 2H), 3.61 (t, J = 6.5 Hz, 2H).
4. a-Keto-esters (87)
[0460] To a three-neck round bottom flask containing Mg turnings (1.2 equiv.)
equipped
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with a magnetic stirrer and dimroth condenser was added a solution of alkyl
bromide 86 (1
equiv.) in anhydrous THE via syringe and external heating under argon
atmosphere. The
reaction mixture was refluxed gently for 30-40 min and then it was cooled to
RT, before
conveying it to a dropping funnel. The Grignard reagent was added dropwise to
a solution of
diethyl oxalate (1.5 equiv.) in THE at -78 C. The reaction mixture was warmed
to 10 C
within 1 hour and then was quenched by the addition of saturated ammonium
chloride
solution. The organic layer was separated, the aqueous layer was extracted
with diethyl ether
and the combined organic layer was washed with brine, dried over MgSO4, and
evaporated.
The residue was purified by flash column chromatography on silica gel (diethyl
ether-hexane)
to give pure compound 87 in 45-65% yields.
5. Selected data of synthesized a-Keto-esters (87)
2-Oxo-6-14-(benzyloxy)phenoxylhexanoic acid ethyl ester (87.3)
10461] 87.3 was confirmed as follows: 'H NMR (500 MHz, CDC13) 8 7.44 (d, J =
7.5 Hz,
2H), 7.40 (t, J = 7.5 Hz, 2H), 7.34 (t, J = 7.5 Hz, 1 H), 6.91 (d, J = 9.0 Hz,
2H), 6.83 (d, J =
9.0 Hz, 2H), 5.03 (s, 2H), 4.33 (q, J = 7.5 Hz, 2H), 3.94 (t, J = 5.8 Hz, 2H),
2.95 (t, J = 7.0
Hz, 2H), 1.90-1.79 (m, 4H), 1.38 (t, J = 7.5 Hz, 3H).
2-Oxo-7-phenoxy-heptanoic acid ethyl ester (87.4)
10462] 87.4 was confirmed as follows: 'H NMR (500 MHz, CDCl3) 8 7.27 (t, J =
7.6 Hz,
2H), 6.93 (t, J = 7.6 Hz, 1H), 6.88 (d, J = 7.6 Hz, 2H), 4.32 (q, J = 7.5 Hz,
2H), 3.96 (t, J =
6.0 Hz, 2H), 2.88 (t, J = 7.5 Hz, 2H), 1.81 (qt, J = 6.5 Hz, 2H), 1.72 (qt, J
= 7.5 Hz, 2H),
1.56-1.49 (in, 2H), 1.37 (t, J = 7.5 Hz, 3H).
6. a,a-Difluoro-esters (88)
104631 To a stirred solution of a-keto-ester 87 (1 equiv.) in anhydrous
chloroform at RT
under an argon atmosphere was added diethylaminosulfur trifluoride (1.1
equiv.). The
reaction mixture was heated under gentle reflux for 3 hours then it was cooled
to RT and
poured into ice-water. The organic layer was separated, washed with sat.
NaHCO3 solution
and dried over MgSO4. Volatiles were removed under reduced pressure and the
crude
product was purified by flash chromatography on silica gel (diethyl ether-
hexane) to give
pure compound 88 in 72-88 % yields.
10464] Alternatively, the reaction mixture was heated using microwave
irradiation (300
W, 100C, 3-5 min). This was followed by work up and purification as described
above to
give compound 88 in 74-86% yields.
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7. Selected data of synthesized a,a-difluoro-esters (88)
2,2-Difluoro-6-13-(benzyloxy)phenoxy]hexanoic acid ethyl ester (88.1)
[0465] 88.1 was confirmed as follows: 'H NMR (500 MHz, CDC13) 6 7.43 (d, J =
7.5 Hz,
2H), 7.38 (t, J = 7.5 Hz, 2H), 7.32 (t, J = 7.5 Hz, 1H), 7.17 (t, J = 8.5 Hz,
1H), 6.57 (dd, J =
8.5 Hz, J = 2.5 Hz, I H), 6.53 (t, J = 2.5 Hz, 1 H), 6.50 (dd, J = 8.5 Hz, J =
2.5 Hz, 1 H), 5.04
(s, 2H), 4.32 (q, J = 7.4 Hz, 2H), 3.94 (t, J = 6.5 Hz, 2H), 2.19-2.08 (m,
2H), 1.82 (qt, J = 7.9
Hz, 2H), 1.71-1.63 (m, 2H), 1.34 (t, J = 7.4 Hz, 3H).
8. a,a-difluoromethylene-ketones (89)
[0466] To a stirred solution of a,a-difluoro-ester 88 (1 equiv.) in anhydrous
THE or
diethyl ether at -78"C under an argon atmosphere was added the appropriate
organolithium or
organomagnesium reagent (1.1-1.5 equiv.) dropwise. The reaction mixture was
allowed to
warm to RT over 1-2 hours period, and then was quenched by the addition of
saturated
ammonium chloride solution. The organic phase was separated, the aqueous layer
was
extracted with diethyl ether or methylene chloride, and the combined organic
layer was
washed with water and brine, dried (MgSO4), and evaporated under reduced
pressure.
Purification by flash column chromatography on silica gel (diethyl ether-
hexane or acetone-
hexane) gave compound 89 in 65-78% yields.
9. Selected data of synthesized a,a-difluoromethyl ene-ketones (89)
3,3-Difluoro-8-phenoxy-2-octanone (89.4)
[04671 89.4 was confirmed as follows: 'H NMR (500 MHz, CDC13) 6 7.28 (m as t,
J =
7.5 Hz,2H),6.93(mas t,J=7.5Hz,1H),6.89(mas d,J= 7.5 Hz,2H),3.96(t,J=6.3Hz,
2H), 2.33 (t, J = 1.5 Hz, 3H), 2.06-1.95 (m, 2H), 1.83-1.77 (m, 2H), 1.56-1.51
(m, 4H).
2,2-Difluoro-8-phenoxy-l-(5-methyl-1.3,4-oxadiazol-2-yl)-octan-l-one (89.7,
mixture of keto and hydrate form in a 2.2:1 ratio)
[04681 89.7 was confirmed as follows: 'H NMR (500 MHz, CDCI3) 8 7.28 (t, J =
7.2 Hz,
2H, keto form), 7.27 (t, J = 7.2 Hz, 2H, hydrate form), 6.93 (t, J = 7.2 Hz,
IH from keto form
and 1H from hydrate form, overlapping), 6.89 (d, J = 7.2 Hz, 2H, hydrate
form), 6.88 (d, J =
7.2 Hz, 2H, keto form), 4.46 (br s, 2H, OH, hydrate form), 3.95 (t, J = 6.5
Hz, 2H, hydrate
form), 3.94 (t, J = 6.5 Hz, 2H, keto form), 2.70 (s, 3H, keto form), 2.60 (s,
3H, hydrate form),
2.44-2.32 (m, 2H, keto form), 2.16-2.00 (m, 2H, hydrate form), 1.82-1.74 (m,
2H from keto
form and 2H from hydrate form, overlapping), 1.64-1.40 (m, 6H from keto form
and 6H from
hydrate form, overlapping); IR (neat) 3237 (br), 2942, 2866, 1734, 1600 cm-'.
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2.2-Difluoro-6-phenoxy- I -(pyridin-2-yl)-hexan- l -one (89.9)
[0469] 89.9 was confirmed as follows: 'H NMR (500 MHz, CDC13) 8 8.65 (m as dt,
J =
6.1 Hz, J = 0.5 Hz, 1H),8.03(mas dt,J=8.0Hz,J=1.0Hz,1H),7.81(ddd,J=8.0Hz,J=
8.0 Hz, J = 1.7 Hz, 1H), 7.44 (ddd, J = 8.0 Hz, J = 6.1 Hz, J = 1.7 Hz, 1H),
7.19 (t, J = 7.8 Hz,
2H), 6.85 (t, J = 7.8 Hz, 1H), 6.78 (d, J = 7.8 Hz, 2H), 3.95 (t, J = 6.5 Hz,
2H), 2.60-2.43 (in,
2H), 1.73 (qt, J = 7.3 Hz, 2H), 1.67-1.62 (in, 2H).
2,2-Difluoro-6-phenoxy-l-(pyridin-3-yl)-hexan-l-one (89.10, hydrate form)
[0470] 89.10 was confirmed as follows: 'H NMR (500 MHz, DMSO-d6) b 8.70 (d, J
=
1.5Hz,1H),8.53(dd,J=5.2Hz,J=1.5Hz,1H),7.88(dt,J=7.6Hz, J= 1.4 Hz,1H),7.39
(dd, J = 7.6 Hz, J = 5.2 Hz, I H),, 7.27 (t, J = 7.4 Hz, 2H), 7.03 (s, 2H),
6.94-6.88 (in, 3H),
3.95 (t, J = 6.2 Hz, 2H), 2.12-1.99 (m, 2H), 1.74 (qt, J = 7.1 Hz, 2H), 1.61-
1.53 (m, 2H).
2,2-Difluoro-6-[3-(benzyloxy)phenoxy1-1-(pyridin-3-yl)-hexan-l-one (89.11,
hydrate form)
[0471] 89.11 was confirmed as follows: 'H NMR (500 MHz, CD3OD) b 8.68 (d, J =
1.7
Hz, I H), 8.52 (dd, J = 5.1 Hz, J = 1.7 Hz, I H), 7.98 (dt, J = 8.0 Hz, J =
1.4 Hz, 1H), 7.46 (dd,
J=8.0Hz,J=5.1Hz,lH),7.42(d,J=7.4Hz,2H),7.36(t,J=7.4Hz,2H),7.29(t,J=7.4
Hz, I H), 7.13 (t, J = 8.2 Hz, 1H),. 6.55 (dd, J = 8.2 Hz, J = 2.5 Hz, I H),
6.51 (t, J = 2.5 Hz,
I H), 6.47 (dd, J = 8.2 Hz, J = 2.5 Hz, I H), 5.04 (s, 2H), 3.92 (t, J = 6.5
Hz, 2H), 2.02 (m,
2H), 1.76 (qt, J = 7.2 Hz, 2H), 1.64 (qt, J = 7.3 Hz, 2H).
Synthesis of a-Keto-esters (91.1-6) and a,a-difluoromethylene-ketones (93.1.
93.2, 93.5,
and 93.7-9)
[0472] a-Keto-esters 91.1-6 as well as a,a-difluoromethylene-ketones 93.1,
93.2, 93.5,
and 93.7-9 were synthesized by the methods depicted in Scheme 21. 4-
Bromobiphenyl
(90.1), bromobenzene (90.2), 3-bromobiphenyl (90.3), 2-bromobiphenyl (90.4),
benzoxazole,
benzothiazole, 2,6-dibromopyridine, and 2-(4-bromophenyl)pyridine were
commercially
available materials. The 2-methyl-oxadiazole (63), benzoxazole, benzothiazole,
2,6-
dibromopyridine, and 2-(4-bromophenyl)pyridine were served as precursors for
the
preparation of the respective organolithium agents using commercially
available n-BuLi.
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Scheme 21
O
R Br a for 90.1, 90.2 R'
or OEt
b for 90.3, 90.4
R2 R3 R2 R3 O
90 91
90.1:R, =Ph,R2=H,R3=H 91.1: R1= Ph, R2 = H, R3 = H
90.2:Ri=H,R2=H,R3=H 91.2:R1=H,R2=H,R3=H
90.3:Ri=H,R2=Ph,R3=H 91.3:R, = H, R2 = Ph, R3 = H
90.4: R1= H, R2 = H, R3 = Ph 91.4: R1= H, R2 = H, R3 Ph
91.5: R1= Br, R2 H,R3=H
91.6: Ri =H, R2 Me, R3 = H
Ri :ftOEt R1 F F
d - R4
R2 R3 O
92 93
N-N
92.1: R1= Ph, R2 = H,R3=H 93.1: R1= Ph, R2= H, R3= H, R4 ~'3
CH
92.2: R, = H, R2 = H, R3 = H
92.3:R1=H,R2=Ph,R3=H N
92.4:Ri=H,R2=H,R3=Ph 93.2:R,=H,R2=H,R3=H,R4= O
92.5: R1 =Br, R2=H, R3=H
N-N
93.5: R1= Br, R2 H, R3 H, R4 CHO 3
N Br
93.7: R,=Ph,R2=H,R3=H, R4=
N
93.8:R1=H,R2=H,R3=H,R4=~S
N
"Cr~'
[0473] Reagents and conditions for the steps in Scheme 21 were as follows:
Step a: Mg,
THF, reflux, then addition to (COOEt)2, THF, -78 C to 10C, 1 hour, 55-65%;
Step b: n-BuLi,
THF, -78 C, 15 min, then addition to (COOEt)2, THF, -78 C to 0 C, 1 hours, 58-
68%; Step c:
DAST CHC13, microwave, 100C, 300 W, 3-5 min, 78-86%; Step d: R.4Li, THF or
Et2O,
-78C to RT, 1-2 hours, 68-80%.
1. a-Keto-esters (91)
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[0474] To a three-neck round bottom flask containing Mg turnings (1.2 equiv.)
equipped
with a magnetic stirrer and dimroth condenser was added a solution of alkyl
bromide 90 (1
equiv.) in anhydrous THE via syringe and external heating under argon
atmosphere. The
reaction mixture was refluxed gently for 30-40 min, and then cooled to RT,
before conveying
it to a dropping funnel. The Grignard reagent was added dropwise to a solution
of diethyl
oxalate (1.5 equiv.) in THE at -78 C. The reaction mixture was warmed to 10"C
within 1
hour, and then quenched by the addition of saturated ammonium chloride
solution. The
organic layer was separated, the aqueous layer was extracted with diethyl
ether, and the
combined organic layer was washed with brine, dried over MgSO4, and
evaporated. The
residue was purified by flash column chromatography on silica gel (diethyl
ether-hexane) to
give pure compound 91 in 55-65% yields.
2. Selected data of synthesized a-Keto-esters (91)
Ethyl 2-(biphenyl-4-yl)-2-oxoacetate (91.1)
[0475] 91.1 was confirmed as follows: 'H NMR (500 MHz, CDC13) 6 8.09 (d, J =
8.5 Hz,
2H), 7.74 (d, J = 8.5 Hz, 2H), 7.65 (d, J = 7.2 Hz, 2H), 7.49 (t, J = 7.2 Hz,
2H), 7.43 (t, J =
7.2 Hz, 1H), 4.47 (q, J = 7.5 Hz, 2H), 1.45 (t, J = 7.5 Hz, 3H).
Ethyl 2-(4-bromophenyl) 2-oxoacetate (91.5)
[0476] 91.5 was confirmed as follows: 'H NMR (500 MHz, CDC13) 6 7.92 (d, J =
8.5 Hz,
2H), 7.68 (d, J = 8.5 Hz, 2H), 3.98 (s, 3H).
3. a,a-Difluoro-esters (92)
[0477] To a solution of a-keto-ester 91 (1 equiv.) in anhydrous chloroform at
RT was
added diethylaminosulfur trifluoride (1.1 equiv.) and the reaction mixture was
heated using
microwave irradiation (300 W. 100 C) for 3-5 min. The reaction mixture was
cooled to RT
and poured into ice-water. The organic layer was separated, washed with sat.
NaHCO3
solution, and then dried over MgSO4. Volatiles were removed under reduced
pressure and
the crude product was purified by flash chromatography on silica gel (diethyl
ether-hexane)
to give pure compound 92 in 78-86 % yields.
4. Selected data of synthesized a,a-difluoro-esters (92)
Ethyl iphenyl-4-yl)-2,2-difluoroacetate (92.1)
[0478] 92.1 was confirmed as follows: 'H NMR (500 MHz, CDC13) 6 7.68 (d, J =
9.0 Hz,
half of AA'BB'system, 2H), 7.66 (d, J = 9.0 Hz, half of AA'BB' system, 2H),
7.58 (d, J = 7.5
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Hz, 2H), 7.46 (t, J = 7.5 Hz, 2H), 7.39 (t, J = 7.5 Hz, 1H), 4.32 (q, J = 7.6
Hz, 2H), 1.33 (t, J =
7.6 Hz, 3H).
Ethyl 2,2-difluoro-2-phenylacetate (92.2)
[0479] 92.2 was confirmed as follows: 'H NMR (500 MHz, CDC13) b 7.62 (d, J =
7.0 Hz,
2H), 7.50-7.43 (rn, 3H), 4.29 (q, J = 7.0 Hz, 2H), 1.29 (t, J = 7.0 Hz, 3H)
Ethyl 2-(biphenyl-3-yl)-2,2-difluoroacetate (92.3)
[0480] 92.3 was confirmed as follows: 'H NMR (500 MHz, CDC13) 6 7.83 (br s,
1H),
7.72 (d, J = 7.0 Hz, I H), 7.58-7.61(m, 3H), 7.53 (t, J = 7.5 Hz, I H), 7.47
(t, J = 7.5 Hz, 2H),
7.39 (t, J = 7.5 Hz, 1H), 4.32 (q, J = 7.5 Hz, 2H), 1.32 (t, J = 7.5 Hz, 3H).
Ethyl 2-(4-bromophenyl)-2,2-difluoroacetate (92.5)
[0481] 92.5 was confirmed as follows: 'H NMR (500 MHz, CDC13) 6 7.61 (d, J =
8.0 Hz,
2H), 7.49 (d, J = 8.0 Hz, 2H), 3.85 (s, 3H).
5. a,a-di fluoromethylene-ketones (93)
[0482] To a stirred solution of a,a-difluoro-ester 92 (1 equiv.) in anhydrous
THE or
diethyl ether at -78 C under an argon atmosphere was added the appropriate
organolithium
reagent (1.1 equiv.) dropwise. The reaction mixture was allowed to warm to RT
over 1-2
hours period, and then quenched by the addition of saturated ammonium chloride
solution.
The organic phase was separated, the aqueous layer was extracted with diethyl
ether or
methylene chloride, and the combined organic layer was washed with water and
brine, dried
(MgSO4), and evaporated under reduced pressure. Purification by flash column
chromatography on silica gel (diethyl ether-hexane or acetone-hexane) gave
compound (89)
in 68-80% yields.
6, Selected data of synthesized a.a-difluoromethylene-ketones (93)
2-(BiphenVl-4-yl)-2,2-difluoro- l -(5-methyl-1,3,4-oxadiazol-2-yl)ethanone
93.1
[0483] 93.1 was confirmed as follows: 'H NMR (500 MHz, acetone-d6) 6 7.73 (d,
J = 8.5
Hz,1H),7.71(d,J=8.0Hz,1H),7.68(d,J=8.5Hz,1H),7.50(t, J = 8.0 Hz, 2H), 7.41 (t,
J
= 8.0 Hz, I H), 2.54 (s, 3)H).
2-(4-Bromophenvl)-2,2-difluoro- l -(5-methyl-1,3,4-oxadiazol-2-ylethanone
93.5
[0484] 93.5 was confirmed as follows: 'H NMR (500 MHz, acetone-d6) S 7.65 (d,
J = 8.0
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Hz, 2H), 7.55 (d, J = 8.0 Hz, 2H), 2.54 (s, 3H).
2-(Biphen vl-4- l6-bromopyridin-2-yl)-2.2-difluoroethanone (93.7)
10485] 93.7 was confirmed as follows: 1H NMR (500 MHz, CDC13) 6 8.03 (dd, J =
7.7
Hz, J = 1.2 Hz, 1H),7.87(d,J=82Hz,2H),7.69(t,J=7.7Hz, I H), 7.67 (d, J = 8.2
Hz,
2H), 7.63 (dd, J = 7.7 Hz, J = 1.2 Hz, I H), 7.59 (d, J = 7.5 Hz, 2H), 7.45
(t, J = 7.5 Hz, 2H),
7.37 (t, J = 7.5 Hz, 1H).
Synthesis of a,a-difluoromethylene-ketones 96.1 and 96.2
[0486] a,a-difluoromethylene-ketones 96.1 and 96.2 were synthesized by the
method
depicted in Scheme 22 using commercially available ethyl brornodi fluoro
acetate, 6-
phenoxyhexyl bromide, and 4-bromobiphenyl.
Scheme 22
O O O
EtOBr a EtO N b R N
F F F F F F
94 95 96
OPh
96.1: R =
96.2: R=
[0487] Reagents and conditions for the steps in Scheme 22 were as follows:
Step a: 2-bromopyridine, Cu, DMSO, 50 C, 2 hours, 82%; Step b: RMgBr, THF, -
78"C to
10C, 1 hour, 50-67%.
1. Ethyl 2-(2-pyrridyl)-2,2-difluoroacetate (95)
[0488] To a solution of ethyl bromodifluoroacetate (1.1 equiv.) and 2-
bromopyridine (1
equiv.) in DMSO was added copper bronze (2.2 equiv.) and the mixture was
heated to 50 C
with stirring for 2 hours. The reaction mixture was cooled to RT and diluted
with ethyl
acetate. A solution of potassium dihydrogen phosphate was added, and the
mixture stirred
for 30 min before filtering. The copper salts were washed with ethyl acetate.
and the organic
layer was washed with water. Solvent evaporation and purification by flash
column
chromatography on silica gel (diethyl ether-hexane) gave the title compound as
a colorless oil
in 82% yield.
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2, a,a-difluoromethvlene-ketones (96)
[04891 To a three-neck round bottom flask containing Mg turnings (1.2 equiv.)
equipped
with a magnetic stirrer and condenser was added a solution of the appropriate
bromide (1
equiv.) in dry THE via syringe. The reaction mixture was refluxed gently for
30-40 min,
cooled to RT, and transferred to the addition funnel. The Grignard reagent was
added
dropwise to a solution of ethyl 2-(2-pyridyl)-2,2-difluoroacetate (1 equiv.)
in THE at -78 C.
The reaction mixture was warned to 10"C within 1 hour and then quenched by the
addition of
saturated ammonium chloride solution. The organic layer was separated, the
aqueous layer
was extracted with diethyl ether, and the combined organic layer was washed
with brine,
dried over MgSO4, and evaporated. The residue was purified by flash column
chromatography on silica gel (diethyl ether-hexane) to give pure compound 96
in 50-67 %
yield.
3. Selected data of synthesized a,a-difluoromethvlene-ketones (96)
1,1-Difluoro-8-phenoxy- l -(pyridin-2-yl)octan-2-one (96.1)
[0490] 96.1 was confirmed as follows: 'H NMR (500 MHz, CDC13) b 8.62 (d, J =
5.0
Hz, 1H),7.84(t,J=7.5Hz, 1H),7.71 (d, J= 5.0 Hz, 1H),7.40(dd,J=7.5Hz,J=5.0Hz,
I H), 7.27 (t, J = 8.3 Hz, 2H), 6.93 (t, J = 8.3 Hz, 1 H), 6.87 (d, J = 8.3
Hz, 2H), 3.94 (t, J = 6.5
Hz, 2H), 2.86 (t, J = 7.5 Hz, 2H), 1.77 (qt, J = 7.5 Hz, 2H), 1.70 (qt, J =
7.0 Hz, 2H), 1.48
(qt, J = 7.0 Hz, 2H), 1.39 (qt, J = 7.4 Hz, 2H).
1-(Biphenyl-4-yl)-2,2-difluoro-2-(pyridin-2-yl)ethanone (96.2)
[04911 96.2 was confirmed as follows: 'H NMR (500 MHz, CDC13) 6 8.63 (d, J =
4.5
Hz, I H), 8.13 (d, J = 8.5Hz, 2H), 7.91 (td, J = 7.5Hz, J = 1.5 Hz, I H), 7.86
(d, J = 8.5Hz,
1H), 7.65 (d, J = 8.5 Hz, 2H), 7.60 (d, J = 7.5Hz, 2H), 7.46 (t, J = 7.5Hz,
2H), 7.38-7.43 (m,
2H).
[04921 IR (neat) = 3060, 1707, 1273, 1146, 906.
[04931 Some of the compounds included in this disclosure were isolated in
their hydrate
form or as mixtures of the keto and the hydrate form. A method for converting
the hydrate to
the keto form is given below.
[0494] A solution of the hydrate form or mixture of hydrate/keto forms in an
anhydrous
solvent (for example benzene) was stirred at RT in the presence of a drying
agent (for
example molecular sieves) for approximately 0.5-4 hours under an argon
atmosphere. The
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drying agent was removed by filtration and the filtrate was evaporated to give
the keto form
quantitatively. Alternatively, the hydrate form or the mixture of hydrate/keto
forms was
dried under high vacuum in the presence of a drying agent (for example P205)
to give the
keto form.
EQUIVALENTS
[04951 Those skilled in the art will recognize, or be able to ascertain, using
no more than
routine experimentation, numerous equivalents to the specific embodiments
described
specifically in this disclosure. Such equivalents are intended to be
encompassed in the scope
of the following claims.
144
